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A single-center randomized, controlled cross-over exercise intervention in 20 women willing to reduce weight (20–40 y, BMI: 27.4 ± 2.1), with the aim to examine potential benefits for weight loss under normal (N-Ox: 20.9%) and mildly reduced (R-Ox: 17.0%) normobaric oxygen in an “Altitude Simulation Chamber”. O2 consumption (VO2), CO2 production (VCO2), blood oxygen saturation (SaO2), blood glucose and lactate (mM) were studied before, during and after cycling for 22 min at a mean personalized workload of 54.2 ± 11.7 watts, about 40% of VO2max. Despite lower absolute SaO2 values and a greater decline from rest to exercise under R-Ox (time x treatment interaction p < 0.01), VO2 did not differ from N-Ox (time x treatment interaction p = 0.178). Average net VO2, 13.8 mL O2 per watt, reflected fairly normal aerobic cycling, irrespective of O2 regime. The Respiratory Exchange Ratio (RER; VO2/VCO2), 0.83 at rest, increased for both treatments to a ratio close to or beyond unity during and directly after exercise (treatment effect p = 0.407). The tendency of cycling for weight loss to clear carbohydrates rather than fat, irrespective of normal or mildly reduced normobaric oxygen, is discussed as a lactate-mediated and phenotype-specific consequence of apparent anaerobic glycolysis with adverse perspectives for weight loss and metabolic health.

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). Methods Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). Results The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue. Conclusion Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT. Funding Agencies|CTSA awardUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [KL2TR002648]; National Center for Advancing Translational SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS)

Non-communicable diseases (NCDs) have risen rapidly worldwide, sparking interest in causative agents and pathways. Patulin (PAT), a xenobiotic found in fruit products contaminated by molds, is postulated to be diabetogenic in animals, but little is known about these effects in humans. This study examined the effects of PAT on the insulin signaling pathway and the pyruvate dehydrogenase complex (PDH). HEK293 and HepG2 cells were exposed to normal (5 mM) or high (25 mM) glucose levels, insulin (1.7 nM) and PAT (0.2 μM; 2.0 μM) for 24 h. The qPCR determined gene expression of key enzymes involved in carbohydrate metabolism while Western blotting assessed the effects of PAT on the insulin signaling pathway and Pyruvate Dehydrogenase (PDH) axis. Under hyperglycemic conditions, PAT stimulated glucose production pathways, caused defects in the insulin signaling pathway and impaired PDH activity. These trends under hyperglycemic conditions remained consistent in the presence of insulin. These findings are of importance, given that PAT is ingested with fruit and fruit products. Results suggest PAT exposure may be an initiating event in insulin resistance, alluding to an etiological role in the pathogenesis of type 2 diabetes and disorders of metabolism. This highlights the importance of both diet and food quality in addressing the causes of NCDs.

Metabolic flexibility is the ability to efficiently adapt metabolism based on nutrient availability and requirement that is essential to maintain homeostasis in times of either caloric excess or restriction and during the energy-demanding state. This regulation is orchestrated in multiple organ systems by the alliance of numerous metabolic pathways under the master control of the insulin-glucagon-sympathetic neuro-endocrine axis. This, in turn, regulates key metabolic enzymes and transcription factors, many of which interact closely with and culminate in the mitochondrial energy generation machinery. Metabolic flexibility is compromised due to the continuous mismatch between availability and intake of calorie-dense foods and reduced metabolic demand due to sedentary lifestyle and age-related metabolic slowdown. The resultant nutrient overload leads to mitochondrial trafficking of substrates manifesting as mitochondrial dysfunction characterized by ineffective substrate switching and incomplete substrate utilization. At the systemic level, the manifestation of metabolic inflexibility comprises reduced skeletal muscle glucose disposal rate, impaired suppression of hepatic gluconeogenesis and adipose tissue lipolysis manifesting as insulin resistance. This is compounded by impaired β-cell function and progressively reduced β-cell mass. A consequence of insulin resistance is the upregulation of the mitogen-activated protein kinase pathway leading to a pro-hypertensive, atherogenic, and thrombogenic environment. This is further aggravated by oxidative stress, advanced glycation end products, and inflammation, which potentiates the risk of micro- and macro-vascular complications. This review aims to elucidate underlying mechanisms mediating the onset of metabolic inflexibility operating at the main target organs and to understand the progression of metabolic diseases. This could potentially translate into a pharmacological tool that can manage multiple interlinked conditions of dysglycemia, hypertension, and dyslipidemia by restoring metabolic flexibility. We discuss the breadth and depth of metabolic flexibility and its impact on health and disease.

DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.

Our objective was to determine the influence of a high-fat diet (HFD) on fasting and postprandial skeletal muscle substrate metabolism in endurance-trained (ET) compared with sedentary (SED) humans. SED ( n = 17) and ET ( n = 7) males were control-fed a 10-day moderate-fat diet followed by a 5-day isocaloric HFD (55% fat, 30% carbohydrate). Skeletal muscle biopsies were taken in the fasted condition and 4 h after a high-fat meal (820 kcals; 63% fat and 25% carbohydrate). Palmitate-induced suppression of pyruvate oxidation, an indication of substrate preference, and oxidation of fat and glucose were measured in homogenized skeletal muscle in fasted and fed states. Postprandial responses were calculated as percent changes from fasting to fed states. Postprandial suppression of pyruvate oxidation was maintained after the HFD in ET, but not SED skeletal muscle, suggesting greater adaptability to dietary intake changes in the former. Fasting total fat oxidation increased due to the HFD in ET skeletal muscle ( P = 0.006), which was driven by incomplete fat oxidation ( P = 0.008). Fasting fat oxidation remained unchanged in skeletal muscle of SED individuals. Yet, postprandial fat oxidation was similar between groups. Fasting glucose oxidation was elevated after the HFD in ET ( P = 0.036), but not SED, skeletal muscle. Postprandial glucose oxidation was reduced due to the HFD in SED ( P = 0.002), but not ET, skeletal muscle. These findings provide insight into differing substrate metabolism responses between SED and ET individuals and highlight the role that the prevailing diet may play in modulating fasting and postprandial metabolic responses in skeletal muscle.NEW & NOTEWORTHY The relationship between high dietary fat intake and physical activity level and their combined effect on skeletal muscle substrate metabolism remains unclear. We assessed the influence of the prevailing diet in modulating substrate oxidation in skeletal muscle of endurance-trained compared with sedentary humans during a high-fat challenge meal. Collectively, our findings demonstrate the adaptability of skeletal muscle in endurance-trained individuals to high dietary fat intake.

Background: It has been known for close to a century that, on average, tumors have a metabolism that is different from those found in healthy tissues. Typically, tumors show a biosynthetic metabolism that distinguishes itself by engaging in large scale aerobic glycolysis, heightened flux through the pentose phosphate pathway, and increased glutaminolysis among other means. However, it is becoming equally clear that non tumorous tissues at times can engage in similar metabolism, while tumors show a high degree of metabolic flexibility reacting to cues, and stresses in their local environment. Scope of the review: In this review, we want to scrutinize historic and recent research on metabolism, comparing and contrasting oncogenic and physiological metabolic states. This will allow us to better define states of bona fide tumor metabolism. We will further contextualize the stress response and the metabolic evolutionary trajectory seen in tumors, and how these contribute to tumor progression. Lastly, we will analyze the implications of these characteristics with respect to therapy response. Major conclusions: In our review, we argue that there is not one single oncogenic state, but rather a diverse set of oncogenic states. These are grounded on a physiological proliferative/wound healing program but distinguish themselves due to their large scale of proliferation, mutations, and transcriptional changes in key metabolic pathways, and the adaptations to widespread stress signals within tumors. We find evidence for the necessity of metabolic flexibility and stress responses in tumor progression and how these responses in turn shape oncogenic progression. Lastly, we find evidence for the notion that the metabolic adaptability of tumors frequently frustrates therapeutic interventions. Keywords: Tumourigenesis, Tumour metabolism, Metabolic flexibility, Central carbon metabolism

The diagnostics of anaerobic glycolytic metabolism which play a subordinate role in elite rowing and parameters such as maximum lactate accumulation rate (νLa.max) have thus far not been associated with ergometer rowing performance. The aim of the study was to quantify the glycolytic energy metabolism (WGly) during a 2000 m ergometer rowing time trial (RTT) and νLa.max during a 10 s maximum ergometer rowing sprint test (RST) and to unravel associations between those variables and RTT performance. Combined post-exercise lactate measurements and oxygen uptake after RST and RTT were used to determine νLa.max and glycolytic energy contribution (WGly) in seven male and three female German U 23 national rowers (N = 10, 19.8 ± 0.9 years, 183.2 ± 7.0 cm height, 79.9 ± 13.3 kg body mass, 16.4 ± 5.1 % body fat). WGly during RTT ranged from 7 to 15.5% and νLa.max between 0.25 and 0.66 mmol∙L−1∙s−1. νLa.max correlated with WGly (p < 0.05, r = 0.74) and the mechanical power output (W) for the first 300 m (300first) during RTT (p < 0.05, r = 0.67). νLa.max further correlated with ∆300first−last (W) for the first and last 300 m (300last) during RTT (p < 0.01, r = 0.87) and also within the subgroup of male rowers. νLa.max displays a wide spectrum of individual differences in rowers. Due to this and its correlation to specific phases of RTT, it contributes to an individual energetic performance profile in rowing. Future studies must undermine the role of νLa.max for exercise performance and whether it serves as a marker that can be specifically targeted for a training-induced increase or decrease.

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.

Context/Objective Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D. Design/Patients Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging. Results T2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P Conclusions Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.

We investigated whether substituting the final half within 60-min bouts of exercise with passive warm or cold water immersion would provide similar or greater benefits for cardiometabolic health. Thirty healthy participants were randomized to two of three short-term training interventions in a partial crossover (12 sessions over 14–16 days, 4 week washout): (i) EXS: 60 min cycling 70% maximum heart rate (HRmax), (ii) WWI: 30 min cycling then 30 min warm water (38–40°C) immersion, and/or (iii) CWI: 30 min cycling then 30 min cold water (10–12°C) immersion. Before and after, participants completed a 20 min cycle work trial, V.O2max test, and an Oral Glucose Tolerance Test during which indirect calorimetry was used to measure substrate oxidation and metabolic flexibility (slope of fasting to post-prandial carbohydrate oxidation). Data from twenty two participants (25 ± 5 year, BMI 23 ± 3 kg/m2, Female = 11) were analyzed using a fixed-effects linear mixed model. V.O2max increased more in EXS (interaction p = 0.004) than CWI (95% CI: 1.1, 5.3 mL/kg/min, Cohen’s d = 1.35), but not WWI (CI: −0.4, 3.9 mL/kg/min, d = 0.72). Work trial distance and power increased 383 ± 223 m and 20 ± 6 W, respectively, without differences between interventions (interaction both p > 0.68). WWI lowered post-prandial glucose ∼9% (CI −1.9, −0.5 mmol/L; d = 0.63), with no difference between interventions (interaction p = 0.469). Substituting the second half of exercise with WWI provides similar cardiometabolic health benefits to time matched exercise, however, substituting with CWI does not.

Producción Científica, Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn2+-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity in the liver, skeletal muscle, and kidneys under fasting (18 h) and refeeding (30 min and 3 h) conditions, in mice fed a standard (SD) or high-fat (HFD) diets. In the liver of mice fed an HFD, fasting reduced IDE protein levels (~30%); whereas refeeding increased its activity (~45%) in both mice fed an SD and HFD. Likewise, IDE protein levels were reduced in the skeletal muscle (~30%) of mice fed an HFD during the fasting state. Circulating lactate concentrations directly correlated with hepatic IDE activity and protein levels. Of note, L-lactate in liver lysates augmented IDE activity in a dose-dependent manner. Additionally, IDE protein levels in liver and muscle tissues, but not its activity, inversely correlated (R2 = 0.3734 and 0.2951, respectively; p < 0.01) with a surrogate marker of insulin resistance (HOMA index). Finally, a multivariate analysis suggests that circulating insulin, glucose, non-esterified fatty acids, and lactate levels might be important in regulating IDE in liver and muscle tissues. Our results highlight that the nutritional regulation of IDE in liver and skeletal muscle is more complex than previously expected in mice, and that fasting/refeeding does not strongly influence the regulation of renal IDE, Ministerio de Economía, Industria y Competitividad (SAF2016-77871-C2-1-R y SAF2016-77871-C2-2-R), Ministerio de Ciencia e Innovación (PID2019-110496RB-C21 y PID2019-110496RB-C22), Junta de Castilla y León (CLU-2019-02), Fundación “la Caixa” (LCF/PR/PR18/51130007)

Aim This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high‐resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial‐venous O2 differences and 31P magnetic resonance spectroscopy (in vivo) and attempt to resolve differences across complementary methodologies as necessary. Methods Data derived from 831 study participants across research published throughout March 2009 to November 2019 were amassed to examine the biological relevance of ex vivo assessments under standard conditions, ie physiological temperatures of 37°C and respiratory chamber oxygen concentrations of ~250 to 500 μmol/L. Results Standard ex vivo‐derived measures are lower (Z ≥ 3.01, P ≤ .0258) en masse than corresponding in vivo‐derived values. Correcting respiratory values to account for mitochondrial temperatures 10°C higher than skeletal muscle temperatures at maximal exercise (~50°C): (i) transforms data to resemble (Z ≤ 0.8, P > .9999) analogous yet context‐specific in vivo measures, eg data collected during maximal 1‐leg knee extension exercise; and (ii) supports the position that maximal skeletal muscle respiratory rates exceed (Z ≥ 13.2, P

Background There is a growing interest among the research community and clinical practitioners to investigate cardiopulmonary exercise test (CPET) procedures and protocols utilized in supine cycling. Materials and Methods The current study investigated the effects of posture on indicators of exercise intensity including gas exchange threshold (GET), respiratory compensation point (RCP), and the rate of peak oxygen uptake (V̇O2 peak), as well as the role of V̇O2 mean response time (MRT) in determining exercise intensity domains in nineteen healthy men (age: 22 ± 3 years). Two moderate-intensity step-transitions from 20 to 100 Watt (W) were completed, followed by a maximal CPET. After completing the ramp test, participants performed a constant-load at 90% of their attained peak power output (PPO). Results No differences were observed in the V̇O2 MRT between the two positions, although the phase II-time constant (τV̇O2p) was 7 s slower in supine position compared to upright (p = 0.001). The rate of O2 uptake in the supine position at GET and RCP were lower compared to the upright position (208 ± 200 mL·min−1 (p = 0.007) and 265 ± 235 mL·min−1 (p = 0.012) respectively). Besides, V̇O2 peak was significantly decreased (by 6%, p = 0.002) during supine position. These findings were confirmed by the wide limits of agreement between the measures of V̇O2 in different postures (V̇O2 peak: −341 to 859; constant-load test: −528 to 783; GET: −375 to 789; RCP: −520 to 1021 all in mL·min−1). Conclusion Since an accurate identification of an appropriate power output (PO) from a single-visit CPET remains a matter of debate, especially for supine cycling, we propose that moderate-intensity step-transitions preceding a ramp CPET could be a viable addition to ensure appropriate exercise-intensity domain determination, in particular upon GET-based prescription.

Cancer cells frequently lack nutrients like glucose, due to insufficient vascular networks. Mitochondrial phosphoenolpyruvate carboxykinase, PCK2, has recently been found to mediate partial gluconeogenesis and hence anabolic metabolism in glucose starved cancer cells. Here we show that PCK2 acts as a regulator of mitochondrial respiration and maintains the redox balance in nutrient-deprived human lung cancer cells. PCK2 silencing increased the abundance and interconversion of tricarboxylic acid (TCA) cycle intermediates, augmented mitochondrial respiration and enhanced glutathione oxidation under glucose and serum starvation, in a PCK2 re-expression reversible manner. Moreover, enhancing the TCA cycle by PCK2 inhibition severely reduced colony formation of lung cancer cells under starvation. As a conclusion, PCK2 contributes to maintaining a reduced glutathione pool in starved cancer cells besides mediating the biosynthesis of gluconeogenic/glycolytic intermediates. The study sheds light on adaptive responses in cancer cells to nutrient deprivation and shows that PCK2 confers protection against respiration-induced oxidative stress., Free Radical Biology and Medicine, 176, ISSN:0891-5849, ISSN:1873-4596

International audience; The liver is a major organ that coordinates the metabolic flexibility of the whole body, which is characterized by the ability to adapt dynamically in response to fluctuations in energy needs and supplies. In this context, hepatocyte mitochondria are key partners in fine-tuning metabolic flexibility. Here we review the metabolic and signalling pathways carried by mitochondria in the liver, the major pathways that regulate mitochondrial function and how they function in health and metabolic disorders associated to obesity, i.e. insulin resistance, non-alcoholic steatosis and steatohepatitis and hepatocellular carcinoma. Finally, strategies targeting mitochondria to counteract liver disorders are discussed.

Aim: Insulin-resistant skeletal muscle is characterized by metabolic inflexibility with associated alterations in substrate selection, mediated by peroxisome-proliferator activated receptor delta (PPARdelta. Although it is established that PPARdelta contributes to the alteration of energy metabolism, it is not clear whether it plays a role in mitochondrial fuel competition. While nutrient overload may impair metabolic flexibility by fuel congestion within mitochondria, in absence of obesity defects at a mitochondrial level have not yet been excluded. We sought to determine whether reduced PPAR content in insulin-resistant rat skeletal muscle of a non-obese rat model of T2DM (Goto-Kakizaki, GK) ameliorate the inhibitory effect of fatty acid (i.e. palmitoylcarnitine) on mitochondrial carbohydrate oxidization (i.e. pyruvate) in muscle fibers. Methods: Bioenergetic function was characterized in oxidative soleus (S) and glycolytic white gastrocnemius (WG) muscles with measurement of respiration rates in permeabilized fibers in the presence of complex I, II, IV and fatty acid substrates. Mitochondrial content was measured by citrate synthase (CS) and succinate dehydrogenase activity (SDH). Western blot was used to determine protein expression of PPARdelta, PDK isoform 2 and 4. Results: CS and SDH activity, key markers of mitochondrial content, were reduced by ~10-30% in diabetic vs control, and the effect was evident in both oxidative and glycolytic muscles. PPARdelta(p

Osteoarthritis (OA) is the most frequent joint disease, however, the etiopathogenesis is still unclear. Chondrocytes rely primarily on glycolysis to meet cellular energy demand, but studies implicate impaired mitochondrial function in OA pathogenesis. The relationship between mitochondrial dysfunction and OA has been established. The aim of the study was to examine the differences in glucose and Fatty Acids (FA) metabolism, especially with regards to metabolic flexibility, in cybrids from healthy (N) or OA donors. Glucose and FA metabolism were studied using D-[14C(U)]glucose and [1-14C]oleic acid, respectively. There were no differences in glucose metabolism among the cybrids. Osteoarthritis cybrids had lower acid-soluble metabolites, reflecting incomplete FA &beta, oxidation but higher incorporation of oleic acid into triacylglycerol. Co-incubation with glucose and oleic acid showed that N but not OA cybrids increased their glucose metabolism. When treating with the mitochondrial inhibitor etomoxir, N cybrids still maintained higher glucose oxidation. Furthermore, OA cybrids had higher oxidative stress response. Combined, this indicated that N cybrids had higher metabolic flexibility than OA cybrids. Healthy donors maintained the glycolytic phenotype, whereas OA donors showed a preference towards oleic acid metabolism. Interestingly, the results indicated that cybrids from OA patients had mitochondrial impairments and reduced metabolic flexibility compared to N cybrids.

Introduction: A family history of type 2 diabetes (FH+) is a major risk factor for the development of insulin resistance and type 2 diabetes. However, it remains unknown whether exercise-induced improvements in insulin sensitivity and metabolic flexibility are impacted by a FH+. Therefore, we investigated whether improvements in insulin sensitivity, metabolic flexibility, body composition, aerobic fitness and muscle strength are limited by a FH+ following eight weeks of combined exercise training compared to individuals without a family history of type 2 diabetes (FH–).Methods: Twenty (n = 10 FH–, n = 10 FH+) young, healthy, sedentary, normoglycemic, Mexican-American males (age: FH– 22.50 ± 0.81, FH+ 23.41 ± 0.86 years; BMI: FH– 27.91 ± 1.55, FH+ 26.64 ± 1.02 kg/m2) underwent eight weeks of combined aerobic and resistance exercise training three times/week (35 min aerobic followed by six full-body resistance exercises). Insulin sensitivity was assessed via hyperinsulinemic euglycemic clamps. Metabolic flexibility was assessed by the change in respiratory quotient from fasted to insulin-stimulated states. Body composition was determined using dual-energy x-ray absorptiometry. Aerobic fitness was determined by a graded exercise test, and upper- and lower-body strength were assessed via one-repetition maximum bench press and leg strength dynamometer, respectively.Results: Insulin sensitivity, metabolic flexibility, aerobic fitness and strength were not different between groups (p > 0.05). Eight weeks of combined aerobic and resistance exercise training improved insulin sensitivity (FH– p = 0.02, FH+ p = 0.002), increased fat free mass (FH– p = 0.006, FH+ p = 0.001), aerobic fitness (FH– p = 0.03, FH+ p = 0.002), and upper- (FH– p = 0.0001, FH+ p = 0.0001) and lower-body strength (FH– p = 0.0009, FH+ p = 0.0003), but did not change metabolic flexibility (p > 0.05) in both groups. Exercise-induced improvements in metabolic outcomes were similar between groups.Conclusions: Insulin sensitivity, metabolic flexibility, aerobic fitness and strength were not compromised by a FH+. Additionally, a FH+ is not a limiting factor for exercise-induced improvements in insulin sensitivity, aerobic fitness, body composition, and strength in normoglycemic young Mexican-American men.

Whereas reactive oxygen species (ROS) can have opposite impacts on insulin signaling, they have mainly been associated with mitochondrial dysfunction in skeletal muscle. We analyzed the relationship between these three features in skeletal muscle of senescence accelerated mice (SAM) prone (P8), which are characterized by enhanced oxidative stress compared to SAM resistant (R1). Oxidative stress, ROS production, antioxidant system, mitochondrial content and functioning, as well as in vitro and in vivo insulin signaling were investigated in gastrocnemius and quadriceps muscles. In SAMP8 compared to SAMR1, muscle content in carbonylated proteins was two-fold (p < 0.01) and ROS production by xanthine oxidase 70% (p < 0.05) higher. Furthermore, insulin-induced Akt phosphorylation measured in vivo and ex vivo as well as muscle glucose uptake measured ex vivo were significantly higher (p < 0.05). Mitochondrial respiration evidenced uncoupling and higher respiration rates with substrates of complexes II and IV, in agreement with higher maximal activity of complexes II and IV (+ 18% and 62%, respectively, p < 0.05). By contrast, maximal activity of complex I was 22% lower (p < 0.05). All strain differences were corrected after 6 months of N-acetylcysteine (NAC) treatment, thus supporting the involvement of high ROS production in these differences. In conclusion in muscle of SAMP8 compared to SAMR1, high ROS production is associated to higher insulin sensitivity and glucose uptake but to lower mitochondrial complex I activity. These conflicting adaptations, with regards to the resulting imbalance between NADH production and use, were associated with intrinsic adjustments in the mitochondrial respiration chain (mitochondrial uncoupling, enhanced complexes II and IV activity). We propose that these bioenergetics adaptations may help at preserving muscle metabolic flexibility of SAMP8.

Background/Objective Impairments in metabolic flexibility and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured metabolic flexibility and substrate handling before and after 8 weeks of overfeeding in initially healthy adults, as a model of the early stages of insulin resistance. Subjects/Methods Twenty-nine healthy men (27 ± 5 years old; BMI 25.5 ± 2.3 kg/m2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6 ± 2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation, and metabolic flexibility were measured in 2 ways: a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter, and b) during a two-step hyperinsulinemic-euglycemic clamp. Results Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (p=0.001 and p=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (0.877 ± 0.020 to 0.864 ± 0.026; p=0.05) and at low insulin levels during the clamp (0.927 ± 0.047 to 0.907 ± 0.032; p=0.01). Overfeeding did not affect metabolic flexibility as measured during a clamp (p≥0.17), but it tended to increase 24-hour metabolic flexibility (awake – sleep RQ) as measured by chamber by 0.010 ± 0.028 (p=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation (13 ± 23 g/day; p=0.003) and tended to increase fat oxidation (6 ± 16 g/day; p=0.07), but did not affect carbohydrate oxidation (p=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, p=8×10−5) but not fat oxidation rates (p=0.09). Conclusions The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

Clostridium acetobutylicum possesses two homologous buk genes, buk (or buk1) and buk2, which encode butyrate kinases involved in the last step of butyrate formation. To investigate the contribution of buk in detail, an in-frame deletion mutant was constructed. However, in all the Delta buk mutants obtained, partial deletions of the upstream ptb gene were observed, and low phosphotransbutyrylase and butyrate kinase activities were measured. This demonstrates that i) buk (CA_C3075) is the key butyrate kinase-encoding gene and that buk2 (CA_C1660) that is poorly transcribed only plays a minor role; and ii) strongly suggests that a Delta buk mutant is not viable if the ptb gene is not also inactivated, probably due to the accumulation of butyryl-phosphate, which might be toxic for the cell. One of the Delta buk Delta ptb mutants was subjected to quantitative transcriptomic (mRNA molecules/cell) and fluxomic analyses in acidogenic, solventogenic and alcohologenic chemostat cultures. In addition to the low butyrate production, drastic changes in metabolic fluxes were also observed for the mutant: i) under acidogenic conditions, the primary metabolite was butanol and a new metabolite, 2-hydroxy-valerate, was produced ii) under solventogenesis, 58% increased butanol production was obtained compared to the control strain under the same conditions, and a very high yield of butanol formation (0.3 g g-(1)) was reached; and iii) under alcohologenesis, the major product was lactate. Furthermore, at the transcriptional level, adhE2, which encodes an aldehyde/alcohol dehydrogenase and is known to be a gene specifically expressed in alcohologenesis, was surprisingly highly expressed in all metabolic states in the mutant. The results presented here not only support the key roles of buk and ptb in butyrate formation but also highlight the metabolic flexibility of C. acetobutylicum in response to genetic alteration of its primary metabolism.

Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism which has been proposed being a benign condition. However, older patients may present with neurological manifestations such as seizures, memory problems, psychiatric problems and/ or cognitive decline. In fibroblasts from CMAMMA patients we have recently demonstrated a dysregulation of energy metabolism with increased dependency on β-oxidation for energy production. Because of the inability of the brain to rely efficiently on this pathway to retrieve the required energy to a great extent, we hypothesize an alternative disease-causing mechanism that does not only include the accumulation of the metabolites malonic and methylmalonic acids. Here, we suggest a novel hypothesis on the possible pathophysiological mechanism responsible for the development of neurological symptoms in the long-run.

Previously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed to characterize the metabolic impact of IR-A and its ligand insulin like growth factor 2 (IGF2) in human breast cancer (BC) cells. To establish autocrine IGF2 action, we generated human BC cells MCF7 overexpressing the human IGF2, while we focused on the metabolic effect of IR-A by stably infecting IGF1R-ablated MCF7 (MCF7IGF1R-ve) cells with a human IR-A cDNA. We then evaluated the expression of key metabolism related molecules and measured real-time extracellular acidification rates and oxygen consumption rates using the Seahorse technology. MCF7/IGF2 cells showed increased proliferation and invasion associated with aerobic glycolysis and mitochondrial biogenesis and activity. In MCF7IGF1R-ve/IR-A cells insulin and IGF2 stimulated similar metabolic changes and were equipotent in eliciting proliferative responses, while IGF2 more potently induced invasion. The combined treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) and the mitochondrial inhibitor metformin blocked cell invasion and colony formation with additive effects. Overall, these results indicate that IGF2 and IR-A overexpression may contribute to BC metabolic reprogramming.

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals’ susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual’s capacity to oxidize dietary fat is a metabolic determinant of weight change.

We assessed metabolic flexibility (MF) via a mixed meal in a group of young, healthy participants with a positive family history of maternal type 2 diabetes (T2D) (FH+) and those without a family history of T2D (FH−) under three distinct conditions; baseline (BL; no previous exercise), 1‐h post high intensity interval exercise (1H), and 48‐h post exercise recovery. On separate visits, participants completed a single bout of high intensity interval exercise (HIIE) and repeated the MMTT 1‐h (1H) and 48 h (48H) postexercise. FH+ participants were not able to suppress fat oxidation 1‐h post exercise (1H) as effectively as FH− participants were, however, this response was improved when measured at the 48H visit. Insulin AUC was significantly lowered at both 1H and 48H when compared to the BL visit. Serum NEFA AUC was elevated 1‐h post exercise, when compared to BL, but was significantly reduced at the 48H visit. Young, healthy participants with a maternal history of T2D demonstrate impaired MF (related to the inability to suppress fat oxidation) in response to acute HIIE (1H) that was improved 48H. The overall effect of HIIE showed improved insulin AUC and NEFA AUC up to 48H post that did not differ by FH.

Bariatric surgery is currently the most effective treatment to reduce excess body weight and obesity related comorbidities. A pre-operative low calorie diet is standard medical practice to induce weight loss and shrink liver size for improved patient safety during surgery, yet not all patients undergoing bariatric surgery respond similarly. In fact, there is large inter-patient variability in surgical outcomes and up to 70% of patients have blunted improvements in cardiometabolic health post-operatively. It has been well established that aerobic exercise can decrease inflammation as well as increase insulin sensitivity, cardiometabolic health, and fitness in obese adults. Therefore, combining pre-operative exercise with standard medical care for 30 days prior to bariatric surgery could elicit greater improvements in surgical outcomes as well as cardiometabolic health and overall well-being at the time of and 30 days after surgery than standard care (SC) alone. The focus of Aim 1 was to examine if increasing cardiorespiratory fitness and insulin sensitivity as well as decreasing inflammation by adding aerobic exercise to SC (EX+SC) improved surgical outcomes and metabolic health 30 days after surgery compared to SC alone in patients receiving bariatric surgery. Despite both treatments improving insulin sensitivity and adiposopathy, a measure of adipose tissue endocrine function, comparably over the study, we found that EX+SC had a shorter length of hospital stay and increased metabolic flexibility post-intervention compared to SC. The pre-operative increase in aerobic fitness was associated with a decrease in operating time and length of hospital stay in bariatric patients. We also showed for the first time that the pre-operative rise in aerobic fitness was linked to preservation of lean mass pre- to post-intervention which was secondarily linked to decreased fat mass and increased post-prandial carbohydrate utilization 30 days post-operation. The objective of Aim 2 was to determine if improving cardiometabolic risk factors prior to bariatric surgery by combining EX with SC compared to SC alone related to surgical outcomes and improved cardiometabolic health 30 days after surgery. Pre-operative SC and EX+SC elicited similar improvements in cardiometabolic disease risk factors throughout the study. However, pre-operative increases in aerobic fitness and lean mass were associated with a decrease in C-reactive protein, a measure of low grade systemic inflammation, 30 days post-operation. In Aim 3, we evaluated the interaction of quality of life, dietary intake, and physical activity as it relates to surgical outcomes and cardiometabolic health responsiveness in bariatric patients receiving pre-operative SC or EX+SC. Patients decreased nutrient intake pre- and post-operatively. Pre-operative SC and EX+SC as well as bariatric surgery was effective at increasing quality of life. Improving pre-operative perceived physical functioning was associated with decreased length of hospital stay. Further, greater adherence to the pre-operative low calorie diet was linked to greater perceived general health 30 days after surgery. Taken together, our findings suggest that EX+SC may be a more effective pre-operatively therapy to reduce length of hospital stay than SC alone. Further, increasing lean mass and aerobic fitness prior to bariatric surgery is important for post-operative responsiveness as these outcomes related to decreased fat mass and systemic inflammation 30 days after surgery.

Background Metabolic reprogramming is a key feature of malignant cells. While glucose is one of the primary substrates for malignant cells, cancer cells also display a remarkable metabolic flexibility. Depending on nutrient availability and requirements, cancer cells will utilize alternative fuel sources to maintain the TCA cycle for bioenergetic and biosynthetic requirements. Lactate was typically viewed as a passive byproduct of cancer cells. However, studies now show that lactate is an important substrate for the TCA cycle in breast, lung, and pancreatic cancer. Methods Metabolic analysis of colorectal cancer (CRC) cells was performed using a combination of bioenergetic analysis and 13C stable isotope tracing. Results We show here that CRC cells use lactate to fuel the TCA cycle and promote growth especially under nutrient-deprived conditions. This was mediated in part by maintaining cellular bioenergetics. Therefore targeting the ability of cancer cells to utilize lactate via the TCA cycle would have a significant therapeutic benefit. Phosphoenolpyruvate carboxykinase (PEPCK) is an important cataplerotic enzyme that promotes TCA cycle activity in CRC cells. Treatment of CRC cells with low micromolar doses of a PEPCK inhibitor (PEPCKi) developed for diabetes decreased cell proliferation and utilization of lactate by the TCA cycle in vitro and in vivo. Mechanistically, we observed that the PEPCKi increased nutrient stress as determined by decreased cellular bioenergetics including decreased respiration, ATP levels, and increased AMPK activation. 13C stable isotope tracing showed that the PEPCKi decreased the incorporation of lactate into the TCA cycle. Conclusions These studies highlight lactate as an important substrate for CRC and the use of PEPCKi as a therapeutic approach to target lactate utilization in CRC cells. Electronic supplementary material The online version of this article (10.1186/s40170-019-0199-6) contains supplementary material, which is available to authorized users.

Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.

Diabetes; Diabetic cardiomyopathy; Heart Diabetis; Cardiomiopatia diabètica; Cor Diabetes; Cardiomiopatía diabética; Corazón Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM. Supported by grants BFU2015-64462R from the Ministerio de Economía y Competitividad (MINECO/FEDER, UE) and HR17-00627 from La Caixa Foundation to J.A.V.

Whilst the human body expends energy constantly, the human diet consists of a mix of carbohydrates and fats delivered in a discontinuous manner. To deal with this sporadic supply of energy, there are transport, storage and utilisation mechanisms, for both carbohydrates and fats, around all tissues of the body. Insulin-resistant states such as type 2 diabetes and obesity are characterised by reduced efficiency of these mechanisms. Exactly how these insulin-resistant states develop, for example whether there is an order in which tissues become insulin resistant, is an active area of research with the hope of gaining a better overall understanding of insulin resistance. In this paper we use a previously derived system of 12 first-or der coupled differential equations that describe the transport between, and storage in, different tissues of the human body. We briefly revisit the derivation of the model before parametrising the model to account for insulin resistance. We then solve the model numerically, separately simulating each individual tissue as insulin resistant, and discuss and compare these results, drawing three main conclusions. The implications of these results are in accordance with biological intuition. First, insulin resistance in a tissue creates a knock-on effect on the other tissues in the body, whereby they attempt to compensate for the reduced efficiency of the insulin resistant tissue. Secondly, insulin resistance causes a fatty liver; and the insulin resistance of tissues other than the liver can cause fat to accumulate in the liver. Finally, although insulin resistance in individual tissues can cause slightly reduced skeletal-muscle metabolic flexibility, it is when the whole body is insulin resistant that the biggest effect on skeletal muscle flexibility is seen

Decreased metabolic flexibility, i.e. a compromised ability to adjust fuel oxidation to fuel availability supports development of adverse consequences of obesity. The aims of this study were (i) to learn whether obesity-resistant A/J and obesity-prone C57BL/6J mice differ in their metabolic flexibility right after weaning; and (ii) to characterize possible differences in control of glucose homeostasis in these animals using glucose tolerance tests (GTT). A/J and C57BL/6J mice of both genders were maintained at 20 °C and weaned to standard low-fat diet at 30 days of age. During the first day after weaning, using several separate animal cohorts, (i) GTT was performed using 1 or 3 mg glucose/g body weight (BW), while glucose was administered either orally (OGTT) or intraperitoneally (IPGTT) at 20 °C; and (ii) indirect calorimetry (INCA) was performed, either in a combination with oral gavage of 1 or 7.5 mg glucose/g BW, or during a fasting/re-feeding transition. INCA was conducted either at 20 °C or 34 °C. Results of both OGTT and IPGTT using 1 mg glucose/g BW at 20 °C, and INCA using 7.5 mg glucose/g BW at 34 °C, indicated higher glucose tolerance and higher metabolic flexibility to glucose, respectively, and lower fasting glycemia in A/J mice as compared with C57BL/6J mice. Thus, control of whole body glucose metabolism between A/J and C57BL/6J mice represents a phenotypic feature differentiating between the strains right after weaning.

Insulin resistance (IR), T2DM, and obesity together form a cluster of interrelated metabolic challenges that may be linked by metabolic inflexibility. Metabolic inflexibility is characterized by the resistance to switching substrate oxidation preference based on substrate availability and can be measured in either fasted or insulin-stimulated conditions. As the largest site for glucose disposal and a primary tissue influencing regulation of blood glucose concentrations, skeletal muscle likely plays a central role in regulating substrate oxidation preference based on substrate availability. Skeletal muscle lipotoxicity caused by an impaired regulation of fat uptake and oxidation is postulated to disrupt insulin signaling and lead to skeletal muscle IR. High dietary saturated fat intake results in reduced basal fat oxidation and a resistance to switching to carbohydrate oxidation during insulin-stimulated conditions in susceptible individuals. This metabolic inflexibility may lead to an accumulation of intramyocellular species that impair insulin signaling. Endurance exercise training improves the capacity for fat oxidation in metabolically inflexible individuals. However, relatively little is known about how endurance exercise training influences substrate oxidation preference when paired with a high fat diet (HFD). Therefore, the purpose of this study was to determine the effects of a HFD on substrate metabolism in skeletal muscle of sedentary and endurance trained (ET) males. Healthy, sedentary (n=17) and ET (n=7) males first consumed a 10-day moderate carbohydrate diet (55% carbohydrate, 30% total fat, 0.05) but decreased in the sedentary (34 ± 7% to 4 ± 5% and 78 ± 26% to -21 ± 6%, respectively; both P0.05). Overall, these findings suggest the ET state attenuates deleterious effects of a short-term HFD on reduced metabolic flexibility and insulin-stimulated glucose oxidation. In addition, a HFD-induced reduction in fat oxidation during the fasted-to-fed transition may be caused by differing mechanisms in sedentary and ET individuals. These findings provide a basis for future work targeting the elucidation of potential mechanistic differences in substrate oxidation preference between sedentary and ET individuals. Ph. D. Type 2 diabetes (T2DM) is a commonly occurring disease worldwide, and treatment of the disease is considerably burdensome for individuals and societies. T2DM is closely related to insulin resistance (IR) and obesity, and in each of these conditions, the characteristic of metabolic inflexibility has been observed. Metabolic inflexibility is a reduced ability to adjust fat or carbohydrate utilization for energy based on the availability of each of these macronutrients. Skeletal muscle may be an important tissue in the regulation of macronutrient utilization since it plays a key role in blood glucose regulation. High dietary saturated fat intake may lead to metabolic inflexibility in skeletal muscle in susceptible individuals. This metabolic inflexibility may result in increased storage of fat within skeletal muscle, which is hypothesized to disrupt insulin signaling. This disruption can lead to IR. Endurance exercise training improves metabolic flexibility. However, little is known about how endurance exercise training influences macronutrient utilization when paired with a high fat diet (HFD). Therefore, the purpose of this study was to determine the effects of a HFD on macronutrient utilization in skeletal muscle of sedentary and endurance trained (ET) males. Seventeen healthy, sedentary males and seven ET males first consumed a 10-day moderate-carbohydrate diet that was provided by the study investigators and designed to keep each participant weight stable. Participants then underwent a high fat challenge testing session in which they consumed a high fat meal and had skeletal muscle biopsies taken both before and after the meal. Participants then consumed a 5-day HFD, also designed to keep them weight stable, and repeated the high fat challenge testing session. Macronutrient utilization measures were performed on the collected skeletal muscle samples. Overall, metabolic flexibility was reduced in the sedentary group but was maintained in the ET group, which suggests that ET individuals may be protected against developing a HFD-induced metabolic inflexibility in skeletal muscle and its associated downstream negative effects on insulin signaling. In addition, fat utilization during the high fat challenge meal decreased in both sedentary and ET individuals as a result of the HFD. However, fat utilization in the fasted state was higher in ET individuals after the HFD compared with baseline, but fat utilization was the same in sedentary individuals before and after the HFD. This suggests there may be differences between sedentary and ET individuals in the mechanisms involved in the adjustment of fat utilization to dietary fat intake. Further research is needed to understand these differences, as they may play important roles in understanding how IR and T2DM develop.

Background Metabolic flexibility is the ability of cells to change substrates for energy production based on the nutrient availability and energy requirement. It has been shown that metabolic flexibility is impaired in obesity and chronic diseases such as type 2 diabetes mellitus, cardiovascular diseases, and metabolic syndrome, although, whether it is a cause or an effect of these conditions remains to be elucidated. Main body In this paper, we have reviewed the literature on metabolic flexibility and curated pathways and processes resulting in a network resource to investigate the interplay between these processes in the subcutaneous adipose tissue. The adipose tissue has been shown to be responsible, not only for energy storage but also for maintaining energy homeostasis through oxidation of glucose and fatty acids. We highlight the role of pyruvate dehydrogenase complex–pyruvate dehydrogenase kinase (PDC-PDK) interaction as a regulatory switch which is primarily responsible for changing substrates in energy metabolism from glucose to fatty acids and back. Baseline gene expression of the subcutaneous adipose tissue, along with a publicly available obesity data set, are visualised on the cellular network of metabolic flexibility to highlight the genes that are expressed and which are differentially affected in obesity. Conclusion We have constructed an abstracted network covering glucose and fatty acid oxidation, as well as the PDC-PDK regulatory switch. In addition, we have shown how the network can be used for data visualisation and as a resource for follow-up studies. Electronic supplementary material The online version of this article (10.1186/s12263-018-0609-3) contains supplementary material, which is available to authorized users.

Metabolic flexibility plays a significant role in energy homeostasis by regulating fuel selection in correspondence to energy demand. Obese and type II diabetic populations have displayed a hindered ability to properly transition from fat oxidation while in a fasted state to carbohydrate oxidation once fed, leading to a buildup of mitochondrial metabolites such as acylcarnitines. Carnitine, essential for fatty acyl-CoA transport through the inner and outer mitochondrial membranes, can be an indicator of mitochondrial distress as elevated levels tend to spill over into plasma suggesting a disruption in oxidation. The current study was designed to examine the effect of short term, high fat feeding on plasma acylcarnitine species diversity and levels and if acylcarnitines are associated with metabolic flexibility. 13 healthy, non-obese, sedentary males, aged 18-40 years participated in this study. Following a 12-hour overnight fast a biopsy was taken from the quadricep before and 4 hours after a high fat meal. Blood draws were obtained pre-biopsy while fasted and every hour for 4 hours post high fat meal consumption. Acylcarnitines from plasma were converted to their butyl esters and analyzed by electrospray ionization tandem mass spectrometry (MS/MS). Changes were observed in acetylcarntine (P=0.0125), glucose oxidation (P=0.0295), C16:1/C16:0 desaturation index (P= 0.0397), and C18:1/C18:0 desaturation index (P=0.0012). We did not find that individual changes in flexibility correlated with circulating acylcarnitine measurements in a fasted state Master of Science

Macronutrient metabolism plays an essential role in the overall health of an individual. Depending on a number of variables, for example, diet, fitness level, or metabolic disease state, protein, carbohydrate and fat have varying capacities to be oxidized and balanced. Further, when analyzing the oxidation of carbohydrate and fat in the skeletal muscle specifically, carbohydrate balance happens quite rapidly, while fat balance does not. The ability of skeletal muscle to adapt and respond to various nutrient states is critical to maintaining healthy metabolic function. Habitual high fat intake has been associated with reduced oxidative capacity, insulin resistance, increased gut permeability, inflammation, and other risk factors often preceding metabolic disease states. The disruption of gut function leads to gut permeability and increases endotoxins released into circulation. Endotoxins have been shown to play an important role in obesity-related whole body and tissue specific metabolic perturbations. Each of these disrupted metabolic processes is known to associate with obesity, metabolic syndrome and diabetes. To date, limited research has investigated the role of high fat diet on skeletal muscle substrate oxidation and its relationship to gut permeability and endotoxins. The purpose of this study was to determine the effects of an acute, five-day, isocaloric high fat diet (HFD) on skeletal muscle substrate metabolism in healthy non-obese humans. An additional purpose was to determine the effects of a HFD on gut permeability and blood endotoxins on healthy, non-obese, sedentary humans. Thirteen college age males were fed a control diet for two weeks, followed by five days of an isocaloric HFD. To assess the effects of a HFD on skeletal muscle metabolic adaptability and postprandial endotoxin levels, subjects underwent a high fat meal challenge before and after a HFD. Muscle biopsies were obtained; blood was collected; insulin sensitivity was assessed via intravenous glucose tolerance test; and intestinal permeability was assessed via the four-sugar probe test before and after the HFD. Postprandial glucose oxidation and fatty acid oxidation in skeletal muscle increased before the HFD intervention but was decreased after. Skeletal muscle in vitro assay of metabolic flexibility was significantly blunted following the HFD. Insulin sensitivity and intestinal permeability were not affected by HFD, but fasting endotoxin was significantly higher following the HFD. These findings demonstrate that in young, healthy males, following five days of an isocaloric high fat diet, skeletal muscle metabolic adaptation is robust. Additionally, increased fasting endotoxin independent of gut permeability changes are potentially a contributor to the inflammatory state that disrupts substrate oxidation. These findings suggest that even short-term changes in dietary fat consumption have profound effects on skeletal muscle substrate metabolism and fasting endotoxin levels, independent of positive energy balance and whole-body insulin sensitivity. Ph. D.

Objective The peptide hormone adropin regulates fuel selection preferences in skeletal muscle under fed and fasted conditions. Here, we investigated whether adropin treatment can ameliorate the dysregulation of fuel substrate metabolism, and improve aspects of glucose homeostasis in diet-induced obesity (DIO) with insulin resistance. Methods DIO C57BL/6 mice maintained on a 60% kcal fat diet received five intraperitoneal (i.p.) injections of the bioactive peptide adropin34-76 (450 nmol/kg/i.p.). Following treatment, glucose tolerance and whole body insulin sensitivity were assessed and indirect calorimetry was employed to analyze whole body substrate oxidation preferences. Biochemical assays performed in skeletal muscle samples analyzed insulin signaling action and substrate oxidation. Results Adropin treatment improved glucose tolerance, enhanced insulin action and augmented metabolic flexibility towards glucose utilization. In muscle, adropin treatment increased insulin-induced Akt phosphorylation and cell-surface expression of GLUT4 suggesting sensitization of insulin signaling pathways. Reduced incomplete fatty acid oxidation and increased CoA/acetyl-CoA ratio suggested improved mitochondrial function. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activated pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulated PDH kinase-4 (PDK-4) that inhibits PDH. Along with these changes, adropin treatment downregulated peroxisome proliferator-activated receptor-gamma coactivator-1α that regulates expression of Cpt1b, Cd36 and Pdk4. Conclusions Adropin treatment of DIO mice enhances glucose tolerance, ameliorates insulin resistance and promotes preferential use of carbohydrate over fat in fuel selection. Skeletal muscle is a key organ in mediating adropin's whole-body effects, sensitizing insulin signaling pathways and altering fuel selection preference to favor glucose while suppressing fat oxidation., Graphical abstract

Aims/hypothesis Insulin-mediated signals and AMP-activated protein kinase (AMPK)-mediated signals are activated in response to physiological conditions that represent energy abundance and shortage, respectively. Focal adhesion kinase (FAK) is implicated in insulin signalling and cancer progression in various non-muscle cell types and plays a regulatory role during skeletal muscle differentiation. The role of FAK in skeletal muscle in relation to insulin stimulation or AMPK activation is unknown. We examined the effects of insulin or AMPK activation on FAK phosphorylation in human skeletal muscle and the direct role of FAK on glucose and lipid metabolism. We hypothesised that insulin treatment and AMPK activation would have opposing effects on FAK phosphorylation and that gene silencing of FAK would alter metabolism. Methods Human muscle was treated with insulin or the AMPK-activating compound 5-aminoimadazole-4-carboxamide ribonucleotide (AICAR) to determine FAK phosphorylation and glucose transport. Primary human skeletal muscle cells were used to study the effects of insulin or AICAR treatment on FAK signalling during serum starvation, as well as to determine the metabolic consequences of silencing the FAK gene, PTK2. Results AMPK activation reduced tyrosine phosphorylation of FAK in skeletal muscle. AICAR reduced p-FAKY397 in isolated human skeletal muscle and cultured myotubes. Insulin stimulation did not alter FAK phosphorylation. Serum starvation increased AMPK activation, as demonstrated by increased p-ACCS222, concomitant with reduced p-FAKY397. FAK signalling was reduced owing to serum starvation and AICAR treatment as demonstrated by reduced p-paxillinY118. Silencing PTK2 in primary human skeletal muscle cells increased palmitate oxidation and reduced glycogen synthesis. Conclusions/interpretation AMPK regulates FAK signalling in skeletal muscle. Moreover, siRNA-mediated FAK knockdown enhances lipid oxidation while impairing glycogen synthesis in skeletal muscle. Further exploration of the interaction between AMPK and FAK may lead to novel therapeutic strategies for diabetes and other chronic conditions associated with an altered metabolic homeostasis. Electronic supplementary material The online version of this article (10.1007/s00125-017-4451-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Skeletal muscle exhibits a remarkable flexibility in the usage of fuel in response to the nutrient intake and energy demands of the organism. In fact, increased physical activity and fasting trigger a transcriptional programme in skeletal muscle cells leading to a switch from carbohydrate to lipid oxidation. Impaired metabolic flexibility has been reported to be associated with obesity and type 2 diabetes, but it is not known whether the disability to adapt to metabolic demands is a cause or a consequence of these pathological conditions. Inasmuch as a poor nutritional environment during early life is a predisposing factor for the development of metabolic diseases in adulthood, in the present study, we aimed to determine the long-term effects of maternal malnutrition on the metabolic flexibility of offspring skeletal muscle. To this end, the transcriptional responses of the soleus and extensor digitorum longus muscles to fasting were evaluated in adult rats born to dams fed a control (17 % protein) or a low-protein (8 % protein, protein restricted (PR)) diet throughout pregnancy and lactation. With the exception of reduced body weight and reduced plasma concentrations of TAG, PR rats exhibited a metabolic profile that was the same as that of the control rats. In the fed state, PR rats exhibited an enhanced expression of key regulatory genes of fatty acid oxidation including CPT1a, PGC-1α, UCP3 and PPARα and an impaired expression of genes that increase the capacity for fat oxidation in response to fasting. These results suggest that impaired metabolic inflexibility precedes and may contribute to the development of metabolic disorders associated with early malnutrition.

Summary The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism., Graphical Abstract, Highlights • TFEB regulates mitochondrial biogenesis and function in muscle • Glucose homeostasis in skeletal muscle requires TFEB • The effects of TFEB on muscle metabolism are independent from PGC1α • TFEB coordinates metabolic flexibility during physical exercise, Mansueto et al. show that TFEB acts as a central coordinator of skeletal muscle insulin sensitivity, glucose homeostasis, lipid oxidation, and mitochondrial function in the adaptive metabolic response to physical exercise in a PGC1α-independent manner.

While research on ocean acidification (OA) impacts on coral reefs has focused on calcification, relatively little is known about effects on coral photosynthesis and respiration, despite these being among the most plastic metabolic processes corals may use to acclimatize to adverse conditions. Here, we present data collected between 2016 and 2018 at three natural CO 2 seeps in Papua New Guinea where we measured the metabolic flexibility (i.e. in hospite photosynthesis and dark respiration) of 12 coral species. Despite some species-specific variability, metabolic rates as measured by net oxygen flux tended to be higher at high p CO 2 ( ca 1200 µatm), with increases in photosynthesis exceeding those of respiration, suggesting greater productivity of Symbiodiniaceae photosynthesis in hospite , and indicating the potential for metabolic flexibility that may enable these species to thrive in environments with high p CO 2 . However, laboratory and field observations of coral mortality under high CO 2 conditions associated with coral bleaching suggests that this metabolic subsidy does not result in coral higher resistance to extreme thermal stress. Therefore, the combined effects of OA and global warming may lead to a strong decrease in coral diversity despite the stimulating effect on coral productivity of OA alone.

Obesity in humans is often associated with metabolic inflexibility, but the underlying molecular mechanisms remain incompletely understood. The aim of the present study was to investigate how adaptation to prolonged fasting affects energy/nutrient-sensing pathways and metabolic gene expression in skeletal muscle from lean and obese individuals. Twelve lean and 14 nondiabetic obese subjects were fasted for 48 h. Whole body glucose/lipid oxidation rates were determined by indirect calorimetry, and blood and skeletal muscle biopsies were collected and analyzed. In response to fasting, body weight loss was similar in both groups, but the decrease in plasma insulin and leptin and the concomitant increase in growth hormone were significantly attenuated in obese subjects. The fasting-induced shift from glucose toward lipid oxidation was also severely blunted. At the molecular level, the expression of insulin receptor-β (IRβ) was lower in skeletal muscle from obese subjects at baseline, whereas the fasting-induced reductions in insulin signaling were similar in both groups. The protein expression of mitochondrial respiratory chain components, although not modified by fasting, was significantly reduced in obese subjects. Some minor differences in metabolic gene expression were observed at baseline and in response to fasting. Surprisingly, fasting reduced AMPK activity in lean but not in obese subjects, whereas the expression of AMPK subunits was not affected. We conclude that whole body metabolic inflexibility in response to prolonged fasting in obese humans is associated with lower skeletal muscle IRβ and mitochondrial respiratory chain content as well as a blunted decline of AMPK activity.

cope Metabolic flexibility is the ability to switch metabolism between carbohydrate oxidation (CHO) and fatty acid oxidation (FAO) and is a biomarker for metabolic health. The effect on metabolic health of nicotinamide riboside (NR) as an exclusive source of vitamin B3 is unknown and is examined here for a wide range of NR. Design and methods Nine-week-old male C57BL/6JRcc mice received a semi-purified mildly obesogenic (40 en% fat) diet containing 0.14% L-tryptophan and either 5, 15, 30, 180, or 900 mg NR per kg diet for 15 weeks. Body composition and metabolic parameters were analyzed. Metabolic flexibility was measured using indirect calorimetry. Gene expression in epididymal white adipose tissue (eWAT) was measured using qRT-PCR . Results The maximum delta respiratory exchange ratio when switching from CHO to FAO (maxΔRERCHO1→FAO) and when switching from FAO to CHO (maxΔRERFAO→CHO2) were largest in 30 mg NR per kg diet (30NR). In eWAT, the gene expression of Pparγ, a master regulator of adipogenesis, and of Sod2 and Prdx3, two antioxidant genes, were significantly upregulated in 30NR compared to 5NR. Conclusion 30NR is most beneficial for metabolic health, in terms of metabolic flexibility and eWAT gene expression, of mice on an obesogenic diet.

Foetal life malnutrition has been studied intensively in a number of animal models. Results show that especially foetal life protein malnutrition can lead to metabolic changes later in life. This might be of particular importance for strict carnivores, for example, cat and mink (Neovison vison) because of their higher protein requirement than in other domestic mammals. This study aimed to investigate the effects of low protein provision during foetal life to male mink kits on their protein metabolism during the early post-weaning period of rapid growth and to investigate whether foetal life protein deficiency affects the response to adequate or deficient protein provision post weaning. Further, we intended to study whether the changes in the gene expression of key enzymes in foetal hepatic tissue caused by maternal protein deficiency were manifested post-weaning. A total of 32 male mink kits born to mothers fed either a low-protein diet (LP), that is, 14% of metabolizable energy (ME) from protein (foetal low – FL), n = 16, or an adequate-protein (AP) diet, that is, 29% of ME from protein (foetal adequate – FA), n = 16) in the last 16.3 ± 1.8 days of pregnancy were used. The FL offspring had lower birth weight and lower relative abundance of fructose-1,6-bisphosphatase (Fru-1,6-P2ase) and pyruvate kinase mRNA in foetal hepatic tissue than FA kits. The mothers were fed a diet containing adequate protein until weaning. At weaning (7 weeks of age), half of the kits from each foetal treatment group were fed an AP diet (32% of ME from protein; n = 8 FA and 8 FL) and the other half were fed a LP diet (18% of ME from protein; n = 8 FA and 8 FL) until 9.5 weeks of age, yielding four treatment groups (i.e. FA-AP, FA-LP, FL-AP and FL-LP). Low protein provision in foetal life lowered the protein oxidation post-weaning compared with the controls (P = 0.006), indicating metabolic flexibility and a better ability to conserve protein. This could not, however, be supported by changes in liver mass because of foetal life experience. A lower relative abundance of Fru-1,6-P2ase mRNA was observed (P < 0.05), being lower in 9.5-week-old FL than in FA kits. It can be concluded that foetal life protein restriction leads to changes in post-weaning protein metabolism through lower protein oxidation of male mink kits.

Item does not contain fulltext BACKGROUND: Pomegranate seed oil has been shown to protect against diet induced obesity and insulin resistance. OBJECTIVE: To characterize the metabolic effects of punicic acid on high fat diet induced obesity and insulin resistance. DESIGN: High-fat diet or high-fat diet with 1% Pomegranate seed oil (PUA) was fed for 12 weeks to induce obesity and insulin resistance. We assessed body weight and composition (pSABRE DEXA-scan), energy expenditure (Columbus Instruments) and insulin sensitivity at the end of the 12 weeks. RESULTS: PSO intake resulted in a lower body weight, 30.5+/-2.9 vs 33.8+/-3.2 g PSO vs HFD respectively, p=0.02, without affecting food intake or energy expenditure. The lower body weight was fully explained by a decreased body fat mass, 3.3+/-2.3 vs 6.7+/-2.7 g for PSO and HFD fed mice, respectively, p=0.02. Insulin clamps showed that PSO did not affect liver insulin sensitivity but clearly improved peripheral insulin sensitivity, 164+/-52% vs 92+/-24% for PSO and HFD fed mice respectively, p=0.01. CONCLUSIONS: We conclude that dietary PSO ameliorates high-fat diet induced obesity and insulin resistance in mice, independent of changes in food intake or energy expenditure. 01 juni 2011

Corpeleijn E, Hessvik NP, Bakke SS, Levin K, Blaak EE, Thoresen GH, Gaster M, Rustan AC. Oxidation of intramyocellular lipids is dependent on mitochondrial function and the availability of extracellular fatty acids. Am J Physiol Endocrinol Metab 299: E14-E22, 2010. First published May 4, 2010; doi:10.1152/ajpendo.00187.2010.-Obesity and insulin resistance are related to both enlarged intramyocellular triacylglycerol stores and accumulation of lipid intermediates. We investigated how lipid overflow can change the oxidation of intramyocellular lipids (ICLOX) and intramyocellular lipid storage (ICL). These experiments were extended by comparing these processes in primary cultured myotubes established from healthy lean and obese type 2 diabetic (T2D) individuals, two extremes in a range of metabolic phenotypes. ICLs were prelabeled for 2 days with 100 mu M [C-14] oleic acid (OA). ICLOX was studied using a (CO2)-C-14 trapping system and measured under various conditions of extracellular OA (5 or 100 mu M) and glucose (0.1 or 5.0 mM) and the absence or presence of mitochondrial uncoupling [carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)]. First, increased extracellular OA availability (5 vs. 100 mu M) reduced ICLOX by 37%. No differences in total lipolysis were observed between low and high OA availability. Uncoupling with FCCP restored ICLOX to basal levels during high OA availability. Mitochondrial mass was positively related to ICLOX, but only in myotubes from lean individuals. In all, a lower mitochondrial mass and lower ICLOX were related to a higher cell-associated OA accumulation. Second, myotubes established from obese T2D individuals showed reduced ICLOX. ICLOX remained lower during uncoupling (P

In vivo insulin sensitivity can be assessed using "open loop" clamp or "closed loop" methods. Open loop clamp methods are static, and fix plasma glucose independently from plasma insulin. Closed loop methods are dynamic, and assess glucose disposal in response to a stable isotope labeled glucose tolerance test. Using PPARalpha(-/-) mice, open and closed loop assessments of insulin sensitivity/glucose disposal were compared. Indirect calorimetry done for the assessment of diurnal substrate utilization/metabolic flexibility showed that chow fed PPARalpha(-/-) mice had increased glucose utilization during the light (starved) cycle. Euglycemic clamps showed no differences in insulin stimulated glucose disposal, whether for chow or high fat diets, but did show differences in basal glucose clearance for chow fed PPARalpha(-/-) versus SV129J-wt mice. In contrast, the dynamic stable isotope labeled glucose tolerance tests reveal enhanced glucose disposal for PPARalpha(-/-) versus SV129J-wt, for chow and high fat diets. Area under the curve for plasma labeled and unlabeled glucose for PPARalpha(-/-) was approximately 1.7-fold lower, P0.01 during the stable isotope labeled glucose tolerance test for both diets. Area under the curve for plasma insulin was 5-fold less for the chow fed SV129J-wt (P0.01) but showed no difference on a high fat diet (0.30 +/- 0.1 for SV129J-wt vs. 0.13 +/- 0.10 for PPARalpha(-/-), P = 0.28). This study demonstrates that dynamic stable isotope labeled glucose tolerance test can assess "silent" metabolic phenotypes, not detectable by the static, "open loop", euglycemic or hyperglycemic clamps. Both open loop and closed loop methods may describe different aspects of metabolic inflexibility and insulin sensitivity.

Acetate is a major product of fermentation processes and an important substrate for sulfate reducing bacteria and methanogenic archaea. Most studies on acetate catabolism by sulfate reducers and methanogens have used pure cultures. Less is known about acetate conversion by mixed pure cultures and the interactions between both groups. We tested interspecies hydrogen transfer and coexistence between marine methanogens and sulfate reducers using mixed pure cultures of two types of microorganisms. First, Desulfovibrio vulgaris subsp. vulgaris (DSM 1744), a hydrogenotrophic sulfate reducer, was cocultured together with the obligate aceticlastic methanogen Methanosaeta concilii using acetate as carbon and energy source. Next, Methanococcus maripaludis S2, an obligate H2- and formate-utilizing methanogen, was used as a partner organism to M. concilii in the presence of acetate. Finally, we performed a coexistence experiment between M. concilii and an acetotrophic sulfate reducer Desulfobacter latus AcSR2. Our results showed that D. vulgaris was able to reduce sulfate and grow from hydrogen leaked by M. concilii. In the other coculture, M. maripaludis was sustained by hydrogen leaked by M. concilii as revealed by qPCR. The growth of the two aceticlastic microbes indicated co-existence rather than competition. Altogether, our results indicate that H2 leaking from M. concilii could be used by efficient H2-scavengers. This metabolic trait, revealed from coculture studies, brings new insight to the metabolic flexibility of methanogens and sulfate reducers residing in marine environments in response to changing environmental conditions and community compositions. Using dedicated physiological studies we were able to unravel the occurrence of less obvious interactions between marine methanogens and sulfate-reducing bacteria. ISSN:1664-302X

During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic disease epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans’ primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.

Background: Metabolic responses are essential for the adaptation of microorganisms to changing environmental conditions. The repertoire of flux responses that the metabolic network can display in different external conditions may be quantified applying flux variability analysis to genome-scale metabolic reconstructions. Results: A procedure is developed to classify and quantify the sources of flux variability. We apply the procedure to the latest Escherichia coli metabolic reconstruction, in glucose minimal medium, with an additional constraint to account for the mechanism coordinating carbon and nitrogen utilization mediated by α-ketoglutarate. Flux variability can be decomposed into three components: internal, external and growth variability. Unexpectedly, growth variability is the only significant component of flux variability in the physiological ranges of glucose, oxygen and ammonia uptake rates. To obtain substantial increases in metabolic flexibility, E. coli must decrease growth rate to suboptimal values. This growth-flexibility trade-off gives a straightforward interpretation to recent work showing that most overall cell-to-cell flux variability in a population of E. coli can be attained sampling a small number of enzymes most likely to constrain cell growth. Importantly, it provides an explanation for the global reorganization occurring in metabolic networks during adaptations to environmental challenges. The calculations were repeated with a pathogenic strain and an old reconstruction of the commensal strain, having less than 50% of the reactions of the latest reconstruction, obtaining the same general conclusions. Conclusions: In E. coli growing on glucose, growth variability is the only significant component of flux variability for all physiological conditions explored. Increasing flux variability requires reducing growth to suboptimal values. The growth-flexibility trade-off operates in physiological and evolutionary adaptations, and provides an explanation for the global reorganization occurring during adaptations to environmental challenges. The results obtained do not rely on the knowledge of kinetic and regulatory details of the system and are highly robust to incomplete or incorrect knowledge of the reaction network.