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Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance, and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography with 18F-fluorodeoxiglucose, which can be dissociated from BAT thermogenic activity, as for example in insulin-resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride lipolysis. This lipolytic BAT response is intertwined with that of white adipose (WAT) and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body's thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically, and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in WAT and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Excessive lean tissue uptake of fatty acids (FAs) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased nonesterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. In this study, 20 individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]palmitate. Hepatic (97 [range 36-215] mmol/6 h vs. 68 [23-132] mmol/6 h, P = 0.03) but not cardiac (11 [range 4-24] mmol/6 h vs. 8 [3-20] mmol/6 h, P = 0.09) uptake of most sources of postprandial FA (NEFA + DFA uptake) integrated over 6 h was higher in IGT versus NGT. DFA accounted for lower fractions of total cardiac (21% [5-47] vs. 25% [9-39], P = 0.08) and hepatic (19% [6-52] vs. 28% [14-50], P = 0.04) uptake in IGT versus NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake and was associated with higher total cardiac FA uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182). [ABSTRACT FROM AUTHOR]

Obesity contributes to reduced life expectancy because of its link with type 2 diabetes and cardiovascular disease. Yet, targeting this poorly diagnosed, ill-defined, and underaddressed modifiable risk factor remains a challenge. In this review, we emphasize that the tendency among health care professionals to amalgam all forms of obesity altogether as a single entity may contribute to such difficulties and discrepancies. Obesity is a heterogeneous condition both in terms of causes and health consequences. Attention should be given to 2 prevalent subgroups of individuals: 1) patients who are overweight or moderately obese with excess visceral adipose tissue; and 2) patients with severe obesity, the latter group having distinct additional health issues related to their large body fat mass. The challenge of tackling high-cardiovascular-risk forms of obesity through a combination of personalized clinical approaches and population-based solutions is compounded by the current obesogenic environment and economy. [ABSTRACT FROM AUTHOR]

Insulin inhibits systemic nonesterified fatty acid (NEFA) flux to a greater degree than glucose or any other metabolite. This remarkable effect is mainly due to insulin-mediated inhibition of intracellular triglyceride (TG) lipolysis in adipose tissues and is essential to prevent diabetic ketoacidosis, but also to limit the potential lipotoxic effects of NEFA in lean tissues that contribute to the development of diabetes complications. Insulin also regulates adipose tissue fatty acid esterification, glycerol and TG synthesis, lipogenesis, and possibly oxidation, contributing to the trapping of dietary fatty acids in the postprandial state. Excess NEFA flux at a given insulin level has been used to define in vivo adipose tissue insulin resistance. Adipose tissue insulin resistance defined in this fashion has been associated with several dysmetabolic features and complications of diabetes, but the mechanistic significance of this concept is not fully understood. This review focusses on the in vivo regulation of adipose tissue fatty acid metabolism by insulin and the mechanistic significance of the current definition of adipose tissue insulin resistance. One hundred years after the discovery of insulin and despite decades of investigations, much is still to be understood about the multifaceted in vivo actions of this hormone on adipose tissue fatty acid metabolism. [ABSTRACT FROM AUTHOR]

The demonstration of metabolically active brown adipose tissue (BAT) in humans primarily using positron emission tomography coupled to computed tomography (PET/CT) with the glucose tracer 18-fluorodeoxyglucose (18FDG) has renewed the interest of the scientific and medical community in the possible role of BAT as a target for the prevention and treatment of obesity and type 2 diabetes (T2D). Here, we offer a comprehensive review of BAT energy metabolism in humans. Considerable advances in methods to measure BAT energy metabolism, including nonesterified fatty acids (NEFA), chylomicron-triglycerides (TG), oxygen, Krebs cycle rate, and intracellular TG have led to very good quantification of energy substrate metabolism per volume of active BAT in vivo. These studies have also shown that intracellular TG are likely the primary energy source of BAT upon activation by cold. Current estimates of BAT's contribution to energy expenditure range at the lower end of what would be potentially clinically relevant if chronically sustained. Yet, 18FDG PET/CT remains the gold-standard defining method to quantify total BAT volume of activity, used to calculate BAT's total energy expenditure. Unfortunately, BAT glucose metabolism better reflects BAT's insulin sensitivity and blood flow. It is now clear that most glucose taken up by BAT does not fuel mitochondrial oxidative metabolism and that BAT glucose uptake can therefore be disconnected from thermogenesis. Furthermore, BAT thermogenesis is efficiently recruited upon repeated cold exposure, doubling to tripling its total oxidative capacity, with reciprocal reduction of muscle thermogenesis. Recent data suggest that total BAT volume may be much larger than the typically observed 50–150 ml with 18FDG PET/CT. Therefore, the current estimates of total BAT thermogenesis, largely relying on total BAT volume using 18FDG PET/CT, may underestimate the true contribution of BAT to total energy expenditure. Quantification of the contribution of BAT to energy expenditure begs for the development of more integrated whole body in vivo methods. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes is one of the leading non-infectious diseases worldwide and closely relates to excess adipose tissue accumulation as seen in obesity. Specifically, hypertrophic expansion of adipose tissues is related to increased cardiometabolic risk leading to type 2 diabetes. Studying mechanisms underlying adipocyte hypertrophy could lead to the identification of potential targets for the treatment of these conditions. Results: We present iTC1390adip, a highly curated metabolic network of the human adipocyte presenting various improvements over the previously published iAdipocytes1809. iTC1390adip contains 1390 genes, 4519 reactions and 3664 metabolites. We validated the network obtaining 92.6% accuracy by comparing experimental gene essentiality in various cell lines to our predictions of biomass production. Using flux balance analysis under various test conditions, we predict the effect of gene deletion on both lipid droplet and biomass production, resulting in the identification of 27 genes that could reduce adipocyte hypertrophy. We also used expression data from visceral and subcutaneous adipose tissues to compare the effect of single gene deletions between adipocytes from each compartment. Conclusions: We generated a highly curated metabolic network of the human adipose tissue and used it to identify potential targets for adipose tissue metabolic dysfunction leading to the development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: IL-15 is an inflammatory cytokine secreted by many cell types. IL-15 is also produced during physical exercise by skeletal muscle and has been reported to reduce weight gain in mice. Contrarily, our findings on IL-15 knockout (KO) mice indicate that IL-15 promotes obesity. The aim of this study is to investigate the mechanisms underlying the pro-obesity role of IL-15 in adipose tissues. Methods: Control and IL-15 KO mice were maintained on high fat diet (HFD) or normal control diet. After 16 weeks, body weight, adipose tissue and skeletal mass, serum lipid levels and gene/protein expression in the adipose tissues were evaluated. The effect of IL-15 on thermogenesis and oxygen consumption was also studied in primary cultures of adipocytes differentiated from mouse preadipocyte and human stem cells. Results: Our results show that IL-15 deficiency prevents diet-induced weight gain and accumulation of lipids in visceral and subcutaneous white and brown adipose tissues. Gene expression analysis also revealed elevated expression of genes associated with adaptive thermogenesis in the brown and subcutaneous adipose tissues of IL-15 KO mice. Accordingly, oxygen consumption was increased in the brown adipocytes from IL-15 KO mice. In addition, IL-15 KO mice showed decreased expression of pro-inflammatory mediators in their adipose tissues. Conclusions: Absence of IL-15 results in decreased accumulation of fat in the white adipose tissues and increased lipid utilization via adaptive thermogenesis. IL-15 also promotes inflammation in adipose tissues that could sustain chronic inflammation leading to obesity-associated metabolic syndrome. [ABSTRACT FROM AUTHOR]

The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through the clinical use of the radioactive glucose analog 18F-fluorodeoxyglucose with PET. This has led to numerous studies demonstrating cold exposure as the major physiological modulator of BAT activity. These reports also suggested that age, gender, BMI and the presence of diabetes are also important modulators of BAT volume and metabolic activity. Although 18F-fluorodeoxyglucose PET has provided important information on BAT glucose metabolism, other techniques are being developed and applied to assess other aspects of BAT metabolism. Here, we summarize the current understanding of the pathophysiological functions of BAT in humans and discuss some of the strengths and limitations of the current investigational techniques. [ABSTRACT FROM AUTHOR]

Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGT+) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGT-). Measured by [11C]acetate with PET, IGT+ subjects have a significant increase in myocardial oxidative index. IGT+ subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT+ directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT+ versus IGT-. The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism. [ABSTRACT FROM AUTHOR]

Experimental overexposure of lean tissues to fatty acids has been linked to ectopic fat deposition and the development of insulin resistance and impaired glucose-stimulated insulin secretion in animal and human studies. Ectopic fat deposition in lean tissues also spontaneously occurs early during the natural history of Type 2 diabetes. Potential mechanisms for this ectopic fat deposition include impaired lean tissue fatty acid oxidation, in situ synthesis of fatty acids (de novo lipogenesis) and/or overexposure of lean tissues to circulating fatty acids. The latter occurs from at least two different circulating pools: nonesterified fatty acids ('free' fatty acids); and triglyceride-rich lipoproteins (mostly chylomicrons and VLDL). This review will summarize current knowledge from investigation in humans about the potential contribution of these mechanisms to lean tissue fatty acid overexposure in the development of Type 2 diabetes. A special emphasis will be made on adipose tissue control of dietary fatty acid partitioning and on recent advances in noninvasive metabolic imaging of this process. [ABSTRACT FROM AUTHOR]

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A noninvasive method to determine postprandial fatty acid tissue partition may elucidate the link between excess dietary fat and type 2 diabetes. We hypothesized that the positron-emitting fatty acid analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered 18FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant 18FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of 18FTHA in the distal thoracic duct, reaching a peak at time 240 min. 18FTHA mean standard uptake value increased progressively in the liver, heart, quadriceps, and subcutaneous and visceral adipose tissues between time 60 and 240 min. Most circulating 18F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received 18FTHA by gavage, we confirmed that >90% of this tracer reached the circulation as triglycerides. This novel noninvasive method to determine tissue dietary fatty acid distribution in humans should prove useful in the study of the mechanisms leading to lipotoxicity. [ABSTRACT FROM AUTHOR]

AbstractBackground:Several techniques are currently used for measurement of body composition. Bioelectrical impedance assessment (BIA) is a simple, noninvasive method of assessing body composition. We aimed to compare multifrequency hand-to-foot (HF-BIA) and foot-to-foot (FF-BIA) bioelectrical impedance analysis techniques to assess fat-free mass (FFM) in a population with a wide range of body mass indices (BMI).Methods:This was a cross-sectional study of 198 adult subjects. Anthropometric and BIA measures (HF-BIA with Hydra ICF/ECF, Xitron Technologies and FF-BIA with Tanita, model TBF-300A) were recorded after a 12-h fast.Results:Participants had a mean age of 42 years and BMI of 33.5 ± 0.7 (range, 17.7–65.6) kg/m2. Mean FFM with HF-BIA (FFMBIA/HF) and FF-BIA (FFMBIA/FF) were 61.3 ± 1.3 kg and 58.1 ± 0.9 kg, respectively (P< 0.001). In subjects with BMI <25 kg/m2, FFMBIA/FFwas not significantly different compared to FFMBIA/HF(+0.2 kg; P= 0.8). However, FFMBIA/FFwas significantly lower in subjects with BMI 25–30 kg/m2(−2.0 kg; P= 0.009), 30–34 kg/m2(−1.8 kg; P= 0.04), 34–42 kg/m2(−4.7 kg; P< 0.001) and >42 kg/m2(−8.0 kg; P= 0.001). Pearson correlations between both methods were very high for FFM (r= 0.92), fat mass (r= 0.91), and % fat mass (r= 0.85), all P< 0.001. Correlation coefficients for FFM were high in each quintile of BMI. FFMBIA/FFwas the only significant independent predictor of FFMBIA/HF(P< 0.001) in linear regression analyses using clinical and FF-BIA variables, but introducing BMI in the model added precision.Conclusion:FFMBIA/FFcorrelates closely with FFMBIA/HFacross all quintiles of BMI, but FF-BIA gives lower FFM in overweight and obese subjects. [ABSTRACT FROM AUTHOR]

Objective: To assess metabolic and endocrine defects in girls genetically predisposed to polycystic ovary syndrome (PCOS). Design: Controlled cross-sectional study. Setting: University hospital. Patient(s): Nine girls, aged 8–14 years, having a first-degree relative diagnosed with PCOS (PCOSr) and 10 age-matched girls without a family history of PCOS. Intervention(s): None. Main Outcome Measure(s): Insulin sensitivity (ISFSIVGTT) determined by frequently sampled IV glucose tolerance testing (GTT) and insulin-induced nonesterified fatty acid (NEFA) suppression, estimated by the log-linear slope of NEFA levels during the first 20 minutes of GTT. Result(s): In comparison to controls, PCOSr had higher body mass index (BMI) Z-score, waist circumference, and waist-to-height ratio. Levels of the androgen 17α-hydroxyprogesterone (17-OHP) were significantly increased in PCOSr, independent of adiposity, and inversely correlated with ISFSIVGTT. The ISFSIVGTT was decreased and the NEFA suppression was less steep in PCOSr compared with controls, independent of BMI and 17-OHP. The NEFA suppression was more pronounced with increasing ISFSIVGTT, independent of adiposity. Conclusion(s): Girls at high risk of developing PCOS display increased adiposity and 17-OHP levels, but are mainly characterized by global insulin resistance and resistance to insulin-induced suppression of lipolysis that were independent of adiposity and 17-OHP levels. Therefore, genetic predisposition to PCOS may be related to early insulin resistance and adipocyte dysfunction. [ABSTRACT FROM AUTHOR]