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Differences in blood concentration of sex hormones in the follicular (FP) and luteal (LP) phases may influence energy metabolism in women. We compared fasting energy metabolism and sweet taste preference on a representative day of the FP and LP in twenty healthy women (25·3 (sd 5·1) years, BMI: 22·2 (sd 2·2) kg/m2) with regular self-reported menses and without the use of hormonal contraceptives. From the self-reported duration of the three prior menstrual cycles, the predicted FP and LP visits were scheduled for days 5–12 and 20–25 after menses, respectively. The order of the FP and LP visits was randomly assigned. On each visit, RMR and RQ by indirect calorimetry, sweet taste preference by the Monell two-series forced-choice tracking procedure, serum fibroblast growth factor 21 by a commercial ELISA (FGF21, a liver-derived protein with action in energy balance, fuel oxidation and sugar preference) and dietary food intake by a 24-h dietary recall were determined. Serum progesterone and oestradiol concentrations displayed the expected differences between phases. RMR was lower in the FP v. LP (5042 (sd 460) v. 5197 (sd 490) kJ/d, respectively; P = 0·04; Cohen effect size, d rm = 0·33), while RQ showed borderline significant higher values (0·84 (sd 0·05) v. 0·81 (sd 0·05), respectively; P = 0·07; d rm = 0·62). Also, in the FP v. LP, sweet taste preference was lower (12 (sd 8) v. 16 (sd 9) %; P = 0·04; d rm = 0·47) concomitant with higher serum FGF21 concentration (294 (sd 164) v. 197 (sd 104) pg/ml; P < 0·01; d rm = 0·66). The menstrual cycle is associated with changes in energy expenditure, sweet taste preference and oxidative fuel partitioning. [ABSTRACT FROM AUTHOR]

The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide- binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity- associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance., Despite the absence of any overt infection or definitive evidence of autoantigen-mediated immune cell activation during obesity, chronic inflammation in this state is an established instigator of several diseases such [...]

Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this 'metabolic inflexibility' is mostly the consequence of impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated glucose disposal rate (amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high-fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics. fuel selection; insulin sensitivity; mitochondria; lipid oxidation; skeletal muscle

Summary: Glucose, fatty acids, and amino acids among others are oxidized to generate adenosine triphosphate (ATP). These fuels are supplied from the environment (through food intake) and internal depots (through lipolysis, glycogenolysis, and proteolysis) at different rates throughout the day. Complex adaptive systems permit to accommodate fuel oxidation according to fuel availability. This capacity of a cell, tissue, or organism to adapt fuel oxidation to fuel availability is defined as metabolic flexibility (MetF). There are conditions, such as insulin resistance, diabetes, and obesity, in which MetF seems to be impaired. The observation that those conditions are accompanied by mitochondrial dysfunction has set the basis to propose a link between mitochondrial dysfunction, metabolic inflexibility, and metabolic health. We here highlight the evidence about the notion that MetF influences metabolic health. [ABSTRACT FROM AUTHOR]