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We evaluated the effect of diets low in energy density (1 kcal/g) and high in either potatoes (Potato) or pulses (Bean) on blood glucose control in participants with insulin resistance. We hypothesized that the Potato and Bean diets would have equivalent effects. This was an 8-week randomized, parallel design, controlled feeding study comparing Potato and Bean diets (50-55% carbohydrate, 30-35% fat, 15-20% protein). Equivalence was prespecified as the mean change in the blood glucose concentration for Potato that was within ±20% of the Bean diet. Thirty-six participants (age: 18-60 years, body mass index: 25-40 kg/m

Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We employed electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned media (EPS-CM) enhanced glucose-stimulated insulin secretion (GSIS). Transcriptomics and subsequent targeted validation revealed Growth Differentiation Factor 15 (GDF15) as a central component of the skeletal muscle secretome. Exposure to recombinant GDF15 enhanced GSIS in cells, islets, and mice. GDF15 enhanced GSIS by upregulating the insulin secretion pathway in β-cells, which was abrogated in the presence of a GDF15 neutralizing antibody. The effect of GDF15 on GSIS was also observed in islets from GFRAL-deficient mice. Circulating GDF15 was incrementally elevated in patients with pre- and type 2 diabetes and positively associated with C-peptide in humans with overweight/obesity. Six weeks of high intensity exercise training increased circulating GDF15 concentrations, which positively correlated with improvements in β-cell function in patients with type 2 diabetes. Taken together, GDF15 can function as a contraction-induced protein that enhances GSIS through activating the canonical signaling pathway in a GFRAL-independent manner.

Precipitated by chronic psychological stress, immune system dysregulation, and a hyperinflammatory state, the sequelae of postacute COVID-19 (long COVID) include depression and new-onset diabetes. We hypothesize that exercise counters the neuropsychiatric and endocrine sequelae of long COVID by inducing the release of circulating factors that mediate the anti-inflammatory response, support brain homeostasis, and increase insulin sensitivity.

This consensus statement is an update of the 2010 American College of Sports Medicine position stand on exercise and type 2 diabetes. Since then, a substantial amount of research on select topics in exercise in individuals of various ages with type 2 diabetes has been published while diabetes prevalence has continued to expand worldwide. This consensus statement provides a brief summary of the current evidence and extends and updates the prior recommendations. The document has been expanded to include physical activity, a broader, more comprehensive definition of human movement than planned exercise, and reducing sedentary time. Various types of physical activity enhance health and glycemic management in people with type 2 diabetes, including flexibility and balance exercise, and the importance of each recommended type or mode are discussed. In general, the 2018 Physical Activity Guidelines for Americans apply to all individuals with type 2 diabetes, with a few exceptions and modifications. People with type 2 diabetes should engage in physical activity regularly and be encouraged to reduce sedentary time and break up sitting time with frequent activity breaks. Any activities undertaken with acute and chronic health complications related to diabetes may require accommodations to ensure safe and effective participation. Other topics addressed are exercise timing to maximize its glucose-lowering effects and barriers to and inequities in physical activity adoption and maintenance.

Background The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. Methods We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnosis and nutritional status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), Control, and Control with malnutrition, based on malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition. Results 74 subjects met inclusion criteria (PAH:52; PAH-Mal:10; Control:10; Control-Mal:2). 1-octene (PAH-Mal 5.1±1.2, PAH 12.5±11.2; p = 0.005) and ammonia (PAH-Mal 14.6±15.8, PAH 56.2±64.2; p = 0.013) were reduced in PAH-Mal compared to PAH. The combination of 1-octene (p = 0.010) and 3-methylhexane (p = 0.045) distinguished malnutrition in PAH (ROC AUC: 0.8549). Conclusions This proof-of-concept study provides the first evidence that the breath print is altered in malnutrition. Larger, prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting. Clinical relevancy statement Early identification and intervention combats malnutrition. However, malnutrition screening practices are hindered by a lack of a malnutrition biomarker. The breath print describes the molecules released in the exhaled breath and is a novel "tissue" to identify biomarkers of disease. This report identifies that the breath print is altered in patients with malnutrition and implicates potential for its use as a malnutrition screening biomarker. This article is protected by copyright. All rights reserved.

OBJECTIVE The aim of this study was to investigate the long-term effects of medical and surgical treatments of type 2 diabetes mellitus (T2DM) on patient-reported outcomes (PROs). BACKGROUND Robust data on PROs from randomized trials comparing medical and surgical treatments for T2DM are lacking. METHODS The Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that 5 years after randomization, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were superior to intensive medical therapy (IMT) alone in achieving glycemic control in patients with T2DM and obesity. A subset of 104 patients participating in the STAMPEDE trial were administered two generic health-related quality of life (QoL) questionnaires (RAND-36 and EQ-5D-3L) and a diabetes-specific instrument at baseline, and then on an annual basis up to 5 years after randomization. RESULTS On longitudinal analysis, RYGB and SG significantly improved the domains of physical functioning, general health perception, energy/fatigue, and diabetes-related QoL compared with IMT group. In the IMT group, none of the QoL components in the generic questionnaires improved significantly from baseline. No significant long-term differences were observed among the study groups in measures of psychological and social aspects of QoL. On multivariable analysis, independent factors associated with improved general health perception at long-term included baseline general health (P < 0.001), insulin independence at 5 years (P = 0.005), RYGB versus IMT (P = 0.005), and SG versus IMT (P = 0.034). Favorable changes following RYGB and SG were comparable. CONCLUSIONS In patients with T2DM, metabolic surgery is associated with long-term favorable changes in certain PROs compared with IMT, mainly on physical health and diabetes-related domains. Psychosocial well-being warrants greater attention after metabolic surgery.

Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder with high type 2 diabetes (T2D) risk. OSA therapy includes positive airway pressure (PAP) treatment, which resolves breathing events but modestly improves metabolic health. Metformin is recommended for T2D prevention but is not advocated in patients with OSA. Our pilot study evaluated the effects of metformin on glucose metabolism and mitochondrial function in OSA patients. Methods: Sixteen adults (50.5±1.6 years, BMI: 36.4±0.8 kg/m2) with OSA (apnea hypopnea index: 53.2±21.1 events/hour) were randomized to receive placebo (n=8) or metformin (n=8) treatment along with PAP for 3 months in a double-blind parallel-group design. Whole body and adipose tissue-specific insulin sensitivity (IS) was determined by oral glucose tolerance test (OGTT) . Skeletal muscle mitochondrial function was determined by high-resolution respirometry using biopsies obtained at baseline and after 3 months of treatment. Results: Change in whole body IS (Matsuda index) was not different in metformin or placebo treated groups (p=0.46) . However, improved acute phase responses during OGTT - glucose uptake (p=0.02) , insulin release (p=0.03) , and suppressed lipolysis (p=0.03) were observed with metformin treatment relative to control. Increased skeletal muscle mitochondrial function was evident with metformin relative to control. Specifically, metformin increased complex I phosphorylation and complex IV electron transfer capacity. Conclusion: Metformin treatment improves acute phase IS and insulin suppression of lipolysis in OSA patients. Strikingly, metformin improved skeletal muscle mitochondrial function independent of changes in second phase glucose disposal and BMI, indicating improved tissue metabolic function. These data suggest that in patients with OSA, improvement in tissue level metabolic function may precede changes in whole-body IS and metformin may improve metabolism. Disclosure E.R.M.Zunica: None. E.C.Heintz: None. R.C.Hebert: None. M.C.Tanksley: None. E.C.Mader: None. J.P.Kirwan: None. C.L.Axelrod: None. P.Singh: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK123456789) ;National Institute of General Medical Sciences (GM123456789)

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepatic function in mice with obesity and NAFLD. Methods: 6-week-old male C57BL/6J mice were fed a two-choice chow/high-fat diet (HFD) to promote diet-induced obesity. At 16 weeks of age, mice were randomized to (1) sham surgery (Sham) , (2) RYGB, or (3) sham + weight-matched calorie restriction to RYGB (WM) . Mice were euthanized at 36 weeks for determination of NAFLD/NASH and hepatic function. Body weight/composition and food intake were measured weekly during the treatment period. ANCOVA-adjusted energy expenditure (EE) was determined 3 and 17 weeks after treatment. Hepatic lipid content and NAFLD scores were determined from H&E-stained tissue sections. Hepatic enzymes and glycogen content were determined by ELISA. Results: RYGB & WM achieved a similar reduction in body weight relative to baseline. RYGB decreased adiposity to a greater extent than WM relative to baseline and Sham (-4.4±0.6 vs. -1.3±0.6 Δg, P Conclusions: RYGB and WM improve hepatic function and decrease the severity of NAFLD through shared and discrete mechanisms of action. RYGB decreases hepatic lipid content to a greater extent than WM independent of food intake, indicating that evading the expected metabolic adaptation in EE after weight loss likely accounts for the additive hepatic benefit of RYGB. Disclosure C. L. Axelrod: None. I. M. Langohr: None. W. S. Dantas: None. R. Townsend: None. V. L. Albaugh: None. J. P. Kirwan: None. H. Berthoud: None. Funding National Institutes of Health (U54GM104940)

Introduction Patients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain limited due to the challenges of metabolic evaluation during the early postoperative period. The purpose of this investigation was to determine the role of foregut exclusion in the resolution of type 2 diabetes after RYGB. Methods Patients with type 2 diabetes (n = 15) undergoing RYGB had a gastrostomy tube (G-tube) placed in their gastric remnant at time of surgery. Patients were randomized to receive a mixed meal tolerance test via oral or G-tube feeding immediately prior to and 2 weeks after surgery in a repeated measures crossover design. Plasma glucose, insulin, C-peptide, incretin responses, and indices of meal-stimulated insulin secretion and sensitivity were determined. Results Body weight, fat mass, fasting glucose and insulin, and circulating lipids were significantly decreased 2 weeks after surgery. The glycemic response to feeding was reduced as a function of total area under the curve but not after adjustment for the reduction in fasting glucose. Oral feeding significantly enhanced insulin and incretin secretion after RYGB, which was entirely ablated by G-tube feeding. Conclusion Foregut exclusion accounts for the rise in incretin and insulin secretion but may not fully explain the early improvements in glucose metabolism after RYGB surgery.

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70–85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at

Reductions in β-cell number and function contribute to the onset type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) surgery can resolve T2D within days of operation, indicating a weight-independent mechanism of glycemic control. We hypothesized that RYGB normalizes glucose homeostasis by restoring β-cell structure and function. Male Zucker Diabetic Fatty (fa/fa; ZDF) rats were randomized to sham surgery (n = 16), RYGB surgery (n = 16), or pair feeding (n = 16). Age-matched lean (fa/+) rats (n = 8) were included as a secondary control. Postprandial metabolism was assessed by oral glucose tolerance testing before and 27 days after surgery. Fasting and postprandial plasma GLP-1 was determined by mixed meal tolerance testing. Fasting plasma glucagon was also measured. β-cell function was determined in isolated islets by a glucose-stimulated insulin secretion assay. Insulin and glucagon positive areas were evaluated in pancreatic sections by immunohistochemistry. RYGB reduced body weight (P < 0.05) and improved glucose tolerance (P < 0.05) compared with sham surgery. RYGB reduced fasting glucose compared with both sham (P < 0.01) and pair-fed controls (P < 0.01). Postprandial GLP-1 (P < 0.05) was elevated after RYGB compared with sham surgery. RYGB islets stimulated with 20 mM glucose had higher insulin secretion than both sham and pair-fed controls (P < 0.01) and did not differ from lean controls. Insulin content was greater after RYGB compared with the sham (P < 0.05) and pair-fed (P < 0.05) controls. RYGB improves insulin secretion and pancreatic islet function, which may contribute to the remission of type 2 diabetes following bariatric surgery. NEW & NOTEWORTHY The onset and progression of type 2 diabetes (T2D) results from failure to secrete sufficient amounts of insulin to overcome peripheral insulin resistance. Here, we demonstrate that Roux-en-Y gastric bypass (RYGB) restores islet function and morphology compared to sham and pair-fed controls in ZDF rats. The improvements in islet function were largely attributable to enhanced insulin content and secretory function in response to glucose stimulation.

OBJECTIVE The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N = 195) or medical/lifestyle therapy (N = 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c [HbA1c] ≤6.5% for 3 months without usual glucose-lowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m2, and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA1c (Δ = −1.9 ± 2.0 vs. −0.1 ± 2.0%; P < 0.001), fasting plasma glucose (Δ = −52 [−105, −5] vs. −12 [−48, 26] mg/dL; P < 0.001), and BMI (Δ = −8.0 ± 3.6 vs. −1.8 ± 2.9 kg/m2; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). CONCLUSIONS Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used.

Bariatric surgery improves cardiovascular health, which might be partly ascribed to beneficial alterations in the autonomic nervous system. However, it is currently unknown whether benefits from surgery on cardiac autonomic regulation in post-bariatric patients can be further improved by adjuvant therapies, namely exercise. We investigated the effects of a 6-month exercise training program on cardiac autonomic responses in women undergoing bariatric surgery. Sixty-two women eligible for bariatric surgery were randomly allocated to either standard of care (control) or an exercise training intervention. At baseline (PRE) and 3 (POST3) and 9 (POST9) months after surgery, we assessed chronotropic response to exercise (CR%; i.e., percentage change in heart rate from rest to peak exercise) and heart rate recovery (HRR30s, HRR60s, and HRR120s; i.e., decay of heart rate at 30, 60, and 120 s post exercise) after a maximal exercise test. Between-group absolute changes revealed higher CR% (Δ = 8.56%, CI95% 0.22–19.90, P = 0.04), HRR30s (Δ = 12.98 beat/min, CI95% 4.29–21.67, P = 0.01), HRR60s (Δ = 22.95 beat/min, CI95% 11.72–34.18, P = 0.01), and HRR120s (Δ = 34.54 beat/min, CI95% 19.91–49.17, P < 0.01) in the exercised vs. non-exercised group. Our findings demonstrate that exercise training enhanced the benefits of bariatric surgery on cardiac autonomic regulation. These results highlight the relevance of exercise training as a treatment for post-bariatric patients, ensuring optimal cardiovascular outcomes.

BACKGROUND: Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis. METHODS: BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n=15) or sham (n=15) surgery at a median age of 41 days, before development of diabetes. At T1D diagnosis, a subcutaneous insulin pellet was implanted, oral glucose tolerance test was performed 21 days later, and tissues were collected 25 days after onset of T1D. Pancreas and liver tissues were assessed by histology and RT-qPCR. Fecal microbiota composition was analyzed by 16S V4 sequencing. RESULTS: Postoperatively, DJB rats weighed less than sham rats (287.8 vs 329.9 g, P=0.04). In both groups, 14 of 15 rats developed T1D, at similar age of onset (87 days in DJB vs 81 days in sham, P=0.17). There was no difference in oral glucose tolerance, fasting and stimulated plasma insulin and c-peptide levels, and immunohistochemical analysis of insulin positive cells in the pancreas. DJB rats needed 1.3±0.4 insulin implants vs 1.9±0.5 in sham rats (P=0.002). Fasting and glucose stimulated glucagon-like peptide 1 (GLP-1) secretion was elevated after DJB surgery. DJB rats had reduced markers of metabolic stress in liver. After DJB, the fecal microbiome changed significantly, including increases in Akkermansia and Ruminococcus, while the changes were minimal in sham rats. CONCLUSION: DJB does not protect against autoimmune T1D in BBDP/Wor rats, but reduces the need for exogenous insulin and facilitates other metabolic benefits including weight loss, increased GLP-1 secretion, reduced hepatic stress, and altered gut microbiome.

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.

The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.Eighty-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function.BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1-ubiquitin binding and LC3II, P 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P 0.0001) while limiting ER stress (decreased PERK signalling, P 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase-3/9 activation, all P 0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, P 0.001).Mitochondrial uncoupling by agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

Mitochondria are essential to the onset and progression of cancer through energy production, reactive oxygen species regulation, and macromolecule synthesis. Genetic and functional adaptations of mitochondria to the tumor environment drive proliferative and metastatic potential. The advent of DNA and RNA sequencing removed critical barriers to the evaluation of genetic mediators of tumorigenesis. However, to date, methodological approaches to evaluate tumor mitochondrial function remain elusive and require technical proficiency limiting the feasibility, ultimately diminishing diagnostic and prognostic value in both experimental and clinical settings. Here, we outline a simple and rapid method to quantify rates of oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity in freshly excised solid tumor homogenates using high-resolution respirometry. The protocol can be reproducibly applied across species and tumor types as well as adapted to evaluate a diversity of mitochondrial ET pathways. Using this protocol, we demonstrate that mice bearing a luminal B mammary cancer exhibit defective nicotinamide adenine dinucleotide-linked respiration and reliance on succinate to generate adenosine triphosphate via OXPHOS.

OBJECTIVE: Metabolically healthy obesity (MHO) is often defined as the absence of metabolic syndrome in the presence of obesity. However, phenotypic features of MHO are unclear. Insulin sensitivity in MHO was cross-sectionally compared with metabolically unhealthy obesity (MUO) and a reference group of young healthy participants without obesity. METHODS: Sedentary adults (n = 96) undergoing anthropometric, blood chemistries, maximal aerobic capacity, and euglycemic-hyperinsulinemic clamp measurements were classified by BMI (

Triple negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype with limited treatment options. Obesity and insulin resistance are associated with a worse prognosis in those with TNBC. Moringa oleifera (moringa) is a tropical edible plant used for both food and medicinal purposes and found to have anti-obesity and anti-cancer effects in vitro and in preclinical models. The anti-cancer effects of moringa seed extract alone and in combination with chemotherapy were evaluated in immunocompromised female mice with diet-induced obesity bearing MDA-MB-231-derived xenograft tumors. Moringa supplementation protected against high-fat diet- and chemotherapy-induced increases in fasting glucose and improved insulin sensitivity. Moringa supplementation alone did not attenuate tumor growth relative to chemotherapy alone, and in combination worsened tumor progression. Moringa supplementation alone reduced angiogenesis, but this effect was abrogated in combination with chemotherapy. Moringa supplementation may be an effective strategy to improve metabolic health in mice with obesity and TNBC and reduce angiogenesis in tumors, but may have a negative interaction when used as a concurrent complementary therapy. Caution should be taken when considering the consumption of moringa seed extracts while receiving chemotherapy for breast cancer treatment. Further investigations of alternative timings of moringa therapy are warranted.

The extent to which the benefits of bariatric surgery may be maintained by lifestyle changes after surgery is unclear. Our hypothesis is that exercise may sustain some metabolic benefits and counteract some of the adverse effects of surgery. In this review, we present findings supporting the proposition that exercise is key to improving overall health in patients after bariatric surgery.

Many adults receive inadequate sleep, which elevates obesity and type 2 diabetes risk and may hinder benefits of calorie restriction (CR). We hypothesized that short sleepers would experience less weight loss and diminished glycemic benefits compared to adequate sleepers during CR. We performed secondary analyses in participants randomized to 25% CR in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy- Phase 2 (CALERIE 2) trial. Body weight, dual-energy x-ray absorptiometry-measured body composition, fasting glucose, insulin, and HOMA-IR were assessed at baseline, 12, and 24 months. Self-reported sleep duration identified participants with stable sleep as short (≤7 hrs, n=45) or adequate sleepers (>7 hrs, n=65). Sex, BMI, weight, and race-adjusted linear mixed models identified differences over time and between sleepers. Short and adequate sleepers had similar body weight and composition values at all timepoints and experienced equivalent CR-induced reductions over time. Baseline HOMA-IR (1.2 vs. 1.0; P=0.047) was higher in short sleepers, with trends noted for glucose (81.7 vs. 83.5 mg/dL; P=0.093) and insulin (5.7 vs. 4.9 µU/mL; P=0.077). Both phenotypes demonstrated enhanced glycemic control relative to baseline at 12 and 24 months. While there were no 12-month differences in absolute glycemic values between sleepers, initial differences re-emerged at 24 months, with higher HOMA-IR (0.9 vs. 0.7; P=0.01) and insulin concentrations (4.3 vs. 3.4 µU/mL; P Disclosure K. K. Hoddy: None. P. Singh: None. J. L. Dorling: None. R. A. Beyl: None. J. P. Kirwan: None. K. Huffman: None. S. B. Racette: None. S. Das: None. C. K. Martin: Advisory Panel; Self; EHE Health, Board Member; Self; NaturallySlim, Other Relationship; Self; ABGIL, Academy of Nutrition and Dietetics, Research Support; Self; American Society for Nutrition, Leona M. and Harry B. Helmsley Charitable Trust, Lilly, National Institutes of Health, Patient-Centered Outcomes Research Institute, U. S. Department of Agriculture, WW. Funding National Institute on Aging (U01AG022132, U01AG020478, U01AG020487, U01AG020480, R01AG060499, U24AG047121, U24AG047121); Agricultural Research Service (1950-51000-071-01S); American Heart Association (20POST35210907); National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK07247615); National Institute of General Medical Sciences (U54GM104940)

There is limited Level-1 evidence from well-powered randomized controlled trials (RCTs) examining improved glycemic control after metabolic surgery in patients with type 2 diabetes (T2D) and obesity. ARMMS-T2D is a multi-center consortium conducting a follow-up study of 4 merged RCTs in 256 patients with baseline Class 1-3 obesity and T2D, randomly assigned to metabolic surgery (MS;Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric banding) or intensive Medical/Lifestyle Intervention (MLI). Three years after randomization, T2D remission rates were higher after MS than MLI (37.5%, 60/160 vs. 2.6%, 2/76, respectively, P

Roux-en-Y gastric bypass (RYGB) is associated with remission of type 2 diabetes. However, the cellular and molecular mechanisms remain unknown. We hypothesized that RYGB would increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (SIRT1), AMPK/pAMPK, and citrate synthase (CS) protein expression and decrease insulin resistance and these changes would be mediated by sphingolipids, including ceramides and the sphingolipid metabolite sphingosine-1 phosphate (S1P). Male ZDF rats were randomized to RYGB (n = 7) or sham surgery (n = 7) and harvested after 28 days. Total tissue ceramide, ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1), and S1P were quantified in the white gastrocnemius muscle using LC-ESI-MS/MS after separation with HPLC. Total SIRT1, AMPK, PGC-1α, and CS protein expression were measured by Western blot. Body weight, fasting glucose, insulin, and HOMA-IR decreased significantly after RYGB compared with sham control. These changes were paralleled by lower total ceramide (483.7 ± 32.3 vs. 280.1 ± 38.8 nmol/g wwt), C18:0 ceramide subspecies (P

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

The cancer anorexia-cachexia syndrome (CACS) is a common, debilitating condition with limited therapeutic options. The defining feature of CACS is weight loss, which suggests a state of negative energy balance. It is unclear whether this net reduction in energy is due solely to anorexia or if a combination of anorexia and increased energy expenditure (EE) occurs. To address this question, we induced lung cancer in mice and measured changes in food intake, EE, and body composition. Mice with CACS developed reductions in food intake, spontaneous activity, and EE. There was severe atrophy and markers of metabolic dysfunction in the adipose and skeletal muscle tissues as compared to mice without CACS and pair-fed wild-type mice. We used anamorelin fumarate (Ana), a ghrelin receptor agonist, alone or in combination ActRIIB-Fc, a ligand trap for TGF-β/activin family members, to reverse anorexia and skeletal muscle atrophy, respectively. Ana effectively increased food intake and the combination of drugs increased lean mass, restored spontaneous activity, and improved overall survival. These beneficial effects were limited to female mice. Our findings suggest that multimodal, gender-specific, therapies are needed to reverse CACS.

Exercise seems to enhance the beneficial effect of bariatric surgery (RYGB) on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underly these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB or standard of care (RYGB). Insulin sensitivity was assessed by OGTT. Muscle biopsies were obtained at baseline, and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index - RYGB: +123% vs. RYGB + ET: +325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I - RYGB: -41% vs. RYGB + ET: -76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-beta 1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle extracellular matrix remodeling.

Background Muscle atrophy and strength loss are common adverse outcomes following bariatric surgery. This randomized, controlled trial investigated the effects of exercise training on bariatric surgery‐induced loss of muscle mass and function. Additionally, we investigated the effects of the intervention on molecular and histological mediators of muscle remodelling. Methods Eighty women with obesity were randomly assigned to a Roux‐en‐Y gastric bypass (RYGB: n = 40, age = 42 ± 8 years) or RYGB plus exercise training group (RYGB + ET: n = 40, age = 38 ± 7 years). Clinical and laboratory parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6 month, three‐times‐a‐week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post‐surgery (for RYGB + ET). A healthy, lean, age‐matched control group was recruited to provide reference values for selected variables. Results Surgery resulted in a similar (P = 0.66) reduction in lower‐limb muscle strength in RYGB and RYGB+ET (−26% vs. −31%), which was rescued to baseline values in RYGB + ET (P = 0.21 vs. baseline) but not in RYGB (P 0.05 vs. baseline) but not RYGB (P > 0.01 vs. baseline). RYGB + ET showed greater Type I (5187 vs. 3898 μm2, P

Rationale & Objectives Adiposity and physical fitness levels are major drivers of cardiometabolic risk, but these relationships have not been well-characterized in chronic kidney disease (CKD). We examined the associations of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic fat, and physical function with inflammation, insulin resistance, and adipokine levels in patients with CKD. Study Design Prospective cohort study. Setting & Participants Participants with stages 3-5 CKD not receiving maintenance dialysis, followed up at one of 8 clinical sites in the Chronic Renal Insufficiency Cohort (CRIC) Study, and who underwent magnetic resonance imaging of the abdomen at an annual CRIC Study visit (n = 419). Predictors VAT volume, SAT volume, intrahepatic fat, body mass index, waist circumference, and time taken to complete the 400-m walk test (physical function). Outcomes Markers of inflammation (interleukin 1β [IL-1β], IL-6, tumor necrosis factor receptor 1 [TNFR1], and TNFR2), insulin resistance (homeostasis model assessment of insulin resistance), and adipokine levels (adiponectin, total and high molecular weight, resistin, and leptin). Analytical Approach Multivariable linear regression of VAT and SAT volume, intrahepatic fat, and physical function with individual markers (log-transformed values), adjusting for relevant covariates. Results Mean age of the study population was 64.3 years; 41% were women, and mean estimated glomerular filtration rate was 53.2 ± 14.6 (SD) mL/min/1.73 m2. More than 85% were overweight or obese, and 40% had diabetes. Higher VAT volume, SAT volume, and liver proton density fat fraction were associated with lower levels of total and high-molecular-weight adiponectin, higher levels of leptin and insulin resistance, and lower high-density lipoprotein cholesterol and higher serum triglyceride levels. A slower 400-m walk time was associated only with higher levels of leptin, total adiponectin, plasma IL-6, and TNFR1 and did not modify the associations between fat measures and cardiometabolic risk factors. Limitations Lack of longitudinal data and dietary details. Conclusions Various measures of adiposity are associated with cardiometabolic risk factors. Physical function was also associated with the cardiometabolic risk factors studied and does not modify associations between fat measures and cardiometabolic risk factors. Longitudinal studies of the relationship between body fat and aerobic fitness with cardiovascular and kidney disease progression are warranted.

PurposeThe aim of this exploratory study was to investigate whether the degree of weight loss properly reflects improvements in cardiometabolic health among patients who underwent Roux-en-Y gastric bypass.MethodsIn this ancillary analysis from a clinical trial, patients were clustered into tertiles according to the magnitude of the percentage weight loss (1st tertile: “higher weight loss”: −37.1 ± 5.8%; 2nd tertile: “moderate weight loss”: −29.7 ± 1.4%; 3rd tertile: “lower weight loss”: −24.2 ± 2.3%). Delta changes (9 months after surgery-baseline) in clustered cardiometabolic risk (i.e., blood pressure index, fasting glucose, high-density lipoprotein [HDL] and triglycerides [TG]), glycated hemoglobin (HbA1c), homeostasis model assessment (HOMA-IR), and C-reactive protein (CRP) were calculated.ResultsA total of 42 patients who had complete bodyweight data (age = 40 ± 8 year; BMI = 47.8 ± 7.1 kg/m2) were included. Surgery led to substantial weight loss (−37.9 ± 11.3 kg, P < 0,001), and clinically significant improvements in blood pressure index (−17.7 ± 8.2 mmHg, P < 0.001), fasting glucose (−36.6 ± 52.5 mg/dL, P < 0.001), HDL (9.4 ± 7.1 mg/dL, P < 0.001), TG (−35.8 ± 44.1 mg/dL P < 0,001), HbA1c (−1.2 ± 1.6%, P < 0.001), HOMA-IR (−4.7 ± 3.9 mg/dL, P < 0.001) and CRP (−8.5 ± 6.7 μg/mL P < 0.001). Comparisons across tertiles revealed no differences for cardiometabolic risk score, fasting glucose, HbAc1, HOMA-IR, blood pressure index, CRP, HDL, and TG (P > 0.05 for all). Individual variable analysis confirmed cardiometabolic improvements across the spectrum on weight-loss. There were no associations between weight loss and any dependent variable.ConclusionWeight loss following bariatric surgery does not correlate with improvements in cardiovascular risk factors. These findings suggest that weight loss alone may be insufficient to assess the cardiometabolic success of bariatric surgery, and the search for alternate proxies that better predict surgery success are needed.

PURPOSE OF REVIEW: Sleep and obesity share a bidirectional relationship, and weight loss has been shown to enhance sleep. Aiming to extend sleep on its own or as part of a lifestyle intervention may attenuate health consequences of short sleep. This review highlights several sleep extension approaches, discusses feasibility of each, and summarizes findings relevant to obesity. RECENT FINDINGS: Sleep extension in response to experimental sleep restriction demonstrates partial rescue of cardiometabolic dysfunction in some but not all studies. Adequate sleep on a nightly basis may be necessary for optimal health. While, initial sleep extension interventions in habitually short sleepers have been met with obstacles, preliminary findings suggest that sleep extension or sleep hygiene interventions may improve glycemic control, decrease blood pressure, and enhance weight loss. SUMMARY: Sleep extension has the potential to attenuate obesity risk and cardiometabolic dysfunction. There is tremendous opportunity for future research that establishes a minimum threshold for sleep extension effectiveness and addresses logistical barriers identified in seminal studies.

PURPOSE Disruption of the skeletal muscle molecular clock leads to metabolic disease, whereas exercise may be restorative, leading to improvements in metabolic health. The purpose of this study was to evaluate the effects of a 12-wk exercise intervention on skeletal muscle molecular clock machinery in adults with obesity and prediabetes, and determine whether these changes were related to exercise-induced improvements in metabolic health. METHODS Twenty-six adults (age, 66 ± 4.5 yr; body mass index (BMI), 34 ± 3.4 kg·m; fasting plasma glucose, 105 ± 15 mg·dL) participated in a 12-wk exercise intervention and were fully provided isoenergetic diets. Body composition (dual x-ray absorptiometry), abdominal adiposity (computed tomography scans), peripheral insulin sensitivity (euglycemic-hyperinsulinemic clamp), exercise capacity (maximal oxygen consumption), and skeletal muscle molecular clock machinery (vastus lateralis biopsy) were assessed at baseline and after intervention. Gene and protein expression of skeletal muscle BMAL1, CLOCK, CRY1/2, and PER 1/2 were measured by quantitative real-time polymerase chain reaction and Western blot, respectively. RESULTS Body composition (BMI, dual x-ray absorptiometry, computed tomography), peripheral insulin sensitivity (glucose disposal rate), and exercise capacity (maximal oxygen consumption) all improved (P < 0.005) with exercise training. Skeletal muscle BMAL1 gene (fold change, 1.62 ± 1.01; P = 0.027) and PER2 protein expression (fold change, 1.35 ± 0.05; P = 0.02) increased, whereas CLOCK, CRY1/2, and PER1 were unchanged. The fold change in BMAL1 correlated with post-glucose disposal rate (r = 0.43, P = 0.044), BMI (r = -0.44, P = 0.042), and body weight changes (r = -0.44, P = 0.039) expressed as percent delta. CONCLUSIONS Exercise training impacts skeletal muscle molecular clock machinery in a clinically relevant cohort of adults with obesity and prediabetes. Skeletal muscle BMAL1 gene expression may improve insulin sensitivity. Future studies are needed to determine the physiological significance of exercise-induced alterations in skeletal muscle clock machinery.

Introduction: A subset of adults with obesity may be classified as having metabolically healthy obesity (MHO). There is a high conversion rate from the MHO condition to a metabolically unhealthy obesity (MUO) condition over time. The insulin sensitizing effects of exercise across these metabolic states has not been established and may inform more precise obesity treatment. Methods: Sedentary adults (n=43) with obesity, but not diabetes, underwent inpatient testing (anthropometric measurements, blood chemistries, aerobic capacity (VO2MAX), and insulin sensitivity (euglycemic clamp) before and after 12 weeks of aerobic exercise training (5x/week, 60 min/session, ∼85% HRMAX). A metabolic health score (MetScore) was calculated using baseline values (BMI, VO2MAX, HOMA-IR, triglycerides, and cholesterol) to stratify participants with MHO (n= 21; MetScore ≤ 237) or MUO (n=22; MetScore > 237). Linear mixed models determined group differences over time. Results: MHO and MUO groups differed by MetScore at baseline (202 and 325; P0.20, all between groups). Insulin (-2.62 μU/ml; P=0.0185) and HOMA-IR (-0.71; P=0.022) decreased in the group with MUO with no between group differences (P=0.75 and P=0.52, respectively). Conclusion: Aerobic exercise enhances individual components of health similarly in persons with MHO and MUO after 12 weeks. However, those with MUO experienced the greatest collective improvement, thus presenting an opportunity for intervention. Disclosure K.K. Hoddy: None. C.L. Axelrod: None. J.T. Mey: None. A. Hari: None. R.A. Beyl: None. J.P. Kirwan: None. Funding National Institute on Aging (AG012834); National Institute of General Medical Sciences (GM104940); Louisiana Clinical & Translational Science Center (U54-GM104940)

Introduction: Metabolic surgery (MS) results in durable resolution of hyperglycemia in ∼50% of patients with type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) account for more than 90% of all metabolic surgeries, and both have been demonstrated to have greater efficacy when compared to intensive medical and lifestyle therapy (IMT) to improve glycemic control. However, a subset of patients following MS exhibit inadequate weight loss, poor glycemic control, or both. Thus, the purpose of this study was to identify novel biomarkers of biochemical resolution of T2D following IMT and MS. Methods: Plasma samples from ninety patients (49.9±7.6 years, 57.7% female) randomly assigned to receive either IMT (n=30), RYGB (n=30) or SG (n=30) were retrospectively analyzed and quantified by untargeted metabolomic analysis using UPLC-tandem mass spectrometry at baseline (PRE) and 24 months (POST) of treatment. Results: We identified 384 metabolites altered by RYGB, SG and IMT treatment. 2-hydroxybutyrate was significantly decreased following all 3 interventions with a greater decrease in SG and RYGB at POST (p≤0.05). Pyruvate was significant lower in the IMT and RYGB group (p≤0.05), but not in SG at POST (vs. PRE). Markers of fatty acid metabolism, including acetylcarnitine and 3-hydroxybutyrate (BHBA), were also decreased following the SG intervention (p≤0.05). Several primary and secondary bile acid metabolites were significantly increased after RYGB compared to SG. Conclusion: We identified a novel metabolomic fingerprint characterizing the longer-term adaptations to IMT, RYGB, and SG. Notably, the metabolomic profile of both RYGB and SG procedures were distinct, suggesting that the roughly equivalent weight loss is achieved by divergent mechanisms. Disclosure W.S. Dantas: None. C.L. Axelrod: None. A. Hari: None. S. Kashyap: Other Relationship; Self; GI Dynamics Inc. P. Schauer: Advisory Panel; Self; GI Dynamics Inc. Consultant; Self; Ethicon US, LLC, Medtronic. Research Support; Self; Ethicon US, LLC, Medtronic. J.P. Kirwan: None. Funding Ethicon

Introduction: Type 2 diabetes (T2D) and obesity reduce healthspan in part by increasing risk of cardiovascular events including arrhythmias, heart attacks, cardiomyopathies, and coronary heart disease. Low protein diets and specific amino acid deficiencies, such as dietary methionine, have been observed to reduce body weight, improve glycemic control, and ultimately extend lifespan. However, little is known of how systemic protein deficiency may alter myocardial integrity and bioenergetic function. Methods: Twelve-month-old male C57BL/6J mice were randomized to a normal protein (NP; 20% casein), low protein (LP; 5% casein), high fat (HF; 60% fat), or high fat + low protein (HF + LP; 60% fat, 5% casein) diet for 16 weeks. Body weight was measured weekly. Oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacity was determined in permeabilized myocardial fiber bundles by high-resolution respirometry. Citrate synthase activity was determined by kinetic enzymatic assay. Cardiomyocyte diameter was determined by haemotoxylin and eosin (H&E) staining. Untargeted transcriptomic profiling was conducted by RNA sequencing. Changes in protein expression were determined by immunoblotting. Results: LP reduced body weight relative to NP and HF, whereas HF+LP reduced body weight relative to HF, but was greater than LP alone. LP and LP+HF increased heart weight relative to body weight and cardiomyocyte diameter relative to both NP and HF. Succinate linked OXPHOS and ETS (complex II coupled and uncoupled) was reduced in both LP and LP+HF compared to NP and HF alone. Conclusion: Protein restriction reduces cardiac OXPHOS capacity and induces cardiomyocyte hypertrophy in aging mice. These results question the applicability of chronic protein restriction for management of obesity-related diseases. Further investigation is required to determine if the alterations in cardiac bioenergetic function and structure are advantageous or maladaptive responses. Disclosure C.L. Axelrod: None. W.S. Dantas: None. G. Davuluri: None. W.T. King: None. C.M. Hill: None. C. Morrison: None. J.P. Kirwan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK105032); National Institute of General Medical Sciences (GM104940)

Exercise seems to enhance the beneficial effect of bariatric surgery (RYGB) on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underly these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB or standard of care (RYGB). Insulin sensitivity was assessed by OGTT. Muscle biopsies were obtained at baseline, and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index - RYGB: +123% vs. RYGB + ET: +325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I - RYGB: -41% vs. RYGB + ET: -76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-beta 1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle extracellular matrix remodeling.

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

Worldwide prevalence of adult overweight and obesity is a growing public health issue. Adults with overweight/obesity often have chronic musculoskeletal pain. Using a mixed-methods review, we aimed to quantify the effectiveness and explore the appropriateness of weight-loss interventions for this population. Electronic databases were searched for studies published between 01/01/90-01/0716. The review included 14 randomised controlled trials that reported weight and pain outcomes and three qualitative studies that explored perceptions of adults with co-existing overweight/obesity and CMP. The random-effects pooled mean weight-loss was 4.9kg (95%CI:2.9,6.8) greater for intervention vs control. The pooled mean reduction in pain was 7.3/100units (95%CI:4.1,10.5) greater for intervention vs control. Study heterogeneity was substantial for weight loss (I2=95%, tau={plusmn}3.5kg) and pain change (I2=67%, tau={plusmn}4.1%). Meta-regression slopes for the predictors of study quality, mean age and baseline mean weight on mean study weight reduction were shallow and not statistically significant (P>0.05). The meta-regression slope between mean pain reduction and mean weight lost was shallow, and not statistically significant, -0.09kg per unit pain score change (95%CI:-0.21,0.40,p=0.54). Meta-synthesis of qualitative findings resulted in two synthesized findings; the importance of healthcare professionals understanding the effects of pain on ability to control weight, and developing management/education programmes that address comorbidity.

Metabolic surgery has emerged as an important therapeutic option for the treatment of type 2 diabetes mellitus, particularly in patients who are obese [(1)][1]. Although observational data had suggested the efficacy of metabolic surgery in promoting improved glycemic, blood pressure, and lipid

Background There are limited data from randomized control trials to support or refute the contention that whole-grains can enhance protein metabolism in humans. Objectives To examine: 1) the clinical effects of a whole-grain diet on whole-body protein turnover; 2) the cellular effects of whole-grains on protein synthesis in skeletal muscle cells; and 3) the population effects of whole-grain intake on age-related muscle loss. Methods Adults with overweight/obesity (n = 14; age = 40 ± 7 y; BMI = 33 ± 5 kg/m2) were recruited into a crossover, randomized controlled trial (NCT01411540) in which isocaloric, macronutrient-matched whole-grain and refined-grain diets were fully provisioned for two 8-wk periods. Diets differed only in the presence of whole-grains (50 g/1000 kcal). Whole-body protein kinetics were assessed at baseline and after each diet in the fasted-state (13C-leucine) and integrated over 24 h (15N-glycine). In vitro studies using C2C12 cells assessed global protein synthesis by surface sensing of translation and anabolic signaling by Western blot. Complementary epidemiological assessments using the NHANES database assessed the effect of whole-grain intake on muscle function assessed by gait speed in older adults (n = 2783). Results Integrated 24-h net protein balance was 3-fold higher on a whole-grain diet compared with a refined-grain diet (P = 0.04). A whole-grain wheat extract increased submaximal rates of global protein synthesis (27%, P < 0.05) in vitro. In a large sample of older adults, whole-grain intake was associated with greater muscle function (OR = 0.92; 95% CI: 0.86, 0.98). Conclusions Consuming 50 g/1000 kcal whole-grains per day promotes greater protein turnover and enhances net protein balance in adults. Whole-grains impact skeletal muscle at the cellular level, and are associated with greater muscle function in older adults. Collectively, these data point to a new mechanism whereby whole-grain consumption favorably enhances protein turnover and improves health outcomes. This clinical trial is registered on clinicaltrials.gov (identifier: NCT01411540)., Whole-body protein balance improves when consuming a whole-grain diet compared with a macronutrient-matched refined-grain diet. Further, whole-grains increase protein synthesis in muscle cells and are related to greater muscle function in older adults.

Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, which was coupled to loss of ATP-stimulated calcium flux and impaired substrate oxidation stimulated by exogenous calcium. The insights obtained herein suggest that DRP1 regulates substrate oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.