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Chronic kidney disease (CKD), a major public health problem, is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of the response to oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. Using targeted metabolic profiling, we examined plasma metabolome in 41 moderate-to-severe non-diabetic CKD patients with estimated glomerular filtration rate (eGFR)2 (38.9±12.7) and 20 healthy controls with normal eGFR (87.2±17.7) before and after 2h of 75g oral glucose load. Compared to controls, CKD participants had higher lactate: pyruvate (L:P) ratio both at fasting and after oral glucose challenge. Total energy production estimated through GTP:GDP ratio was impaired during OGTT despite similar fasting GTP:GDP ratio. CKD group had sustained elevation of vitamin B family members, TCA cycle metabolites, and purine nucleotides in response to glucose challenge. Metabolic profiling in response to OGTT suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into insulin sensitizers in patients with non-diabetic CKD and their impact on energy metabolism.

Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology, and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we 1) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; 2) discuss the interaction between circadian molecular metabolism and TRE; 3) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; 4) summarize other time-related dietary interventions that have been studied in people; and 4) identify current gaps in knowledge and provide a framework for future research directions.

Time-restricted eating (TRE) is a dietary pattern in which daily food intake is restricted to a 6-h period without any caloric intake for the rest of the day. TRE improves glucose homeostasis in animal models even independent of weight loss and calorie intake. However, the weight-loss independent effect of TRE on glucose homeostasis in people remains debatable. We conducted a pilot study to investigate whether TRE without weight loss improves glycemic control and insulin sensitivity in women with prediabetes. Participants were randomized to the TRE (9-h daily eating period) or Control group (15-h daily eating period) for 12 weeks. We studied five participants (TRE n = 3 and Control n = 2) with overweight/obesity, prediabetes, and habitual daily eating period greater than 14 hours ([means and SD] age 50 ± 16 years, BMI 31 ± 5 kg/m2) . The daily eating period decreased in the TRE group (13.8 ± 0.5 vs. 8.5 ± 0.5 h) , but not in the Control group (13.9 ± 0.9 vs. 14.1 ± 1.1 h) . Participants’ weight, diet composition, and number of eating occasions remained unchanged during the study period for both groups. Glycemic control in free-living conditions assessed by using continuous glucose monitoring tended to improve in the TRE group (24-h area under the curve for interstitial glucose concentration: 2572 ± 286 vs. 2161 ± 216 mg/dl/24 h) , but not in the Control group (23± 59 vs. 2374 ± 2mg/dl/24 h) . Skeletal muscle insulin sensitivity assessed by using a hyperinsulinemic-euglycemic clamp procedure tended to increase in the TRE group (median and IQR: 27 (21, 37) vs. 34 (27, 41) μmol/kg/min) , but not in the Control group (41 ± 9 vs. 36 ± μmol/kg/min) . These preliminary results suggest that TRE may lead to weight-loss-independent improvements in glycemic control and insulin sensitivity in women with prediabetes. Further ongoing research will establish the effect of TRE without weight loss on glucose homeostasis and insulin sensitivity in people at high risk for type 2 diabetes mellitus. Disclosure M.Chondronikola: None. S.Zhu: None. P.Surampudi: n/a. B.Roshanravan: None. C.Sanchez: None. Funding NIH-UL1-TR001860, Clinical and Translational Science Center-Highly Innovative Pilot Award and USDA NationalInstitute of Food and Agriculture, Hatch project numberCA-D-NTR-2618-H

Obesity and associated metabolic syndrome are a global public health issue. Understanding the pathophysiology of this systemic disease is of critical importance for the development of future therapeutic interventions to improve clinical outcomes. The multiorgan nature of the pathophysiology of obesity presents a unique challenge. Total-body PET imaging, either static or dynamic, provides a vital set of tools to study organ crosstalk. The visualization and quantification of tissue metabolic kinetics with total-body PET in health and disease provides essential information to better understand disease physiology and potentially develop diagnostic and therapeutic modalities.

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis

Author(s): Chondronikola, Maria | Abstract: Purpose of reviewBrown adipose tissue (BAT) and the thermogenic adipocytes in white adipose tissue (WAT) are considered emerging targets against obesity-related metabolic perturbations given their high capacity for thermogenesis and glucose and lipid disposal. This manuscript summarizes and critically evaluates the recent advances on the role of BAT and thermogenic adipocytes in glucose homeostasis in humans.Recent findingsRecent studies support that BAT has high capacity for glucose disposal not only during cold but during rewarming and thermoneutrality as well. Moreover, BAT is now considered a metabolic sink for the disposal of branched-chain amino acids improving whole-body glucose metabolism in rodents and, potentially, in humans. β3 adrenergic agonism and glucagon-like peptide 1 increase BAT metabolic activity for glucose and/or induce the browning of WAT. Finally, recent findings support the association of glucose disposal in BAT with subclinical atherosclerosis and the reproducibility of two advanced medical imaging methods for the assessment of BAT using a glucose radiotracer.SummaryRecent studies provide new insights on the role of human BAT and thermogenic adipocytes in glucose metabolism. However, further research is needed to unequivocally establish the clinical significance of BAT and the thermogenic adipocytes in glucose homeostasis in humans.

BACKGROUND: An increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear. METHODS: Hepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%. RESULTS: The contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations. CONCLUSIONS: These data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL. TRIAL REGISTRATION: ClinicalTrials.gov NCT02706262. FUNDING: This study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.

Noradrenaline is the primary physiological regulator of adipocyte thermogenesis in response to decreased environmental temperature1. However, the molecular factors and effector pathways that lie downstream of noradrenaline-stimulated thermogenesis are still not fully understood but are purportedly driven by cAMP downstream of β-adrenergic receptor (βAR) activation. Furthermore, while the transcriptional mechanisms regulating Ucp1 are well-characterized2, the transcriptional regulation of UCP1-independent thermogenesis is largely unknown. Here, we show that brown adipose tissue (BAT) is primed to respond to environmental cold by triggering coordinated α-adrenergic receptor (αAR) and βAR signaling to induce the expression of thermogenic genes of the futile creatine cycle3,4. Using fat-specific loss-of-function models, we reveal that EBFs, ERRs, and PGC1α are required for the cold-stimulated transcriptional induction of the futile creatine cycle in vivo. Through the application of chemogenetics, we demonstrate that combined fat-selective Gαs (activated by βARs) and Gαq (activated by αARs) signaling elevates whole-body energy expenditure to a greater extent than either signaling pathway alone in a manner that is dependent on the key effector protein of the futile creatine cycle, CKB3. Moreover, genetic and pharmacological studies reveal that CKB is necessary for nearly all of the α1AR-stimulated component of brown adipocyte-intrinsic respiration and is thus critical for the full activation of noradrenaline-stimulated thermogenesis. Thus, the futile creatine cycle is integrated into facultative and adaptive thermogenesis through coordinated α1AR and β3AR signaling.

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A–Gαq–futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Hyperglycemia during pregnancy and gestational diabetes mellitus (GDM) constitute an important public health problem due to their prevalence and long-term health consequences both for the mother and offspring. Results from studies in rodents and some clinical investigations suggest that meal time manipulation may be a potential lifestyle approach against conditions involving perturbations in glucose homeostasis (e.g., hyperglycemia, insulin resistance, diabetes, etc.). The purpose of this review is to summarize and critically evaluate the current literature on the role of meal timing and daily nutrient distribution on glycemic control during pregnancy. Only a small number of mostly observational studies have assessed the role of meal timing in glucose homeostasis during pregnancy. Food consumption earlier in the day and short-term fasting with adequate nutrient intake may improve glycemic control during the second and third trimester of gestation. Considering that the field of chrononutrition is still in its infancy and many questions remain unanswered, future prospective and carefully designed studies are needed to better understand the role of meal timing in metabolic homeostasis and maternal and fetal health outcomes during pregnancy.

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

Brown adipose tissue (BAT) is an emerging target against obesity and its related metabolic diseases. Wibmer et al.1 recently reported that human BAT is associated with a healthier fat distribution and improved cardiometabolic health independent of adiposity and fat distribution., Brown adipose tissue (BAT) is an emerging target against obesity and its related metabolic diseases. Wibmer et al. recently reported that human BAT is associated with a healthier fat distribution and improved cardiometabolic health independent of adiposity and fat distribution.

Nicotinamide adenine dinucleotide (NAD + ) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD + metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase ( Nampt ) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD + biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD + –SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD + synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD + biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulatinglevels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

The recent re-discovery of brown adipose tissue (BAT) and even more recent discovery of the browning of white adipose tissue (WAT) in humans have generated intense scientific interest in the role of adipose tissue as potential target against obesity and its metabolic complications. The purpose of this review is to: i) critically evaluate the current evidence on the physiological significance of BAT and the browning of WAT in metabolic function in humans and ii) discuss factors that have been reported to regulate BAT and/or the browning of WAT in humans. The current literature supports that BAT and the browning of WAT constitute promising emerging targets for interventions aiming to prevent and/or treat of obesity and its metabolic complications. Further research is needed to better understand the physiological significance of BAT and browning of WAT in health and disease along with the factors modulating their metabolic function in humans.

Obesity and associated metabolic syndrome are a global public health issue. Understanding the pathophysiology of this systemic disease is of critical importance for the development of future therapeutic interventions to improve clinical outcomes. The multiorgan nature of the pathophysiology of obesity presents a unique challenge. Total-body PET imaging, either static or dynamic, provides a vital set of tools to study organ crosstalk. The visualization and quantification of tissue metabolic kinetics with total-body PET in health and disease provides essential information to better understand disease physiology and potentially develop diagnostic and therapeutic modalities.

Purpose of review Intermittent fasting has been proposed as a potential nutrition approach against obesity and metabolic disease. Although data from studies in rodents convincingly support the antiobesity and cardiometabolic benefits of intermittent fasting, its effects in human health are still debatable. Recent findings Recent studies have examined the effect of two intermittent fasting approaches, that is, alternate day fasting (ADF) and time-restricted eating (TRE), on weight loss and cardiometabolic risk factors. ADF seems to be an equally effective weight loss approach to caloric restriction, but adherence to ADF is more challenging. ADF improves cardiometabolic risk factors, whereas it may have superior metabolic benefits compared to caloric restriction in people with insulin resistance. TRE with ad libitum food intake is well tolerated and induces 2-4% weight loss in approximatively 3 months. Additionally, TRE may have metabolic benefits particularly in people with metabolically abnormal obesity even without weight loss. Summary Intermittent fasting is a promising nutritional approach against obesity and its related metabolic diseases. Further research is needed to: i) establish the long-term effectiveness of TRE in weight loss and metabolic health, ii) improve the long-term adherence to ADF and investigate its weight loss independent effects in metabolic health, and iii) determine the mechanisms underlying the potential cardiometabolic benefits of intermittent fasting in humans.

Intramyocellular triglyceride (imTG) in skeletal muscle plays a significant role in metabolic health, and an infusion of [(13)C(16)]palmitate can be used to quantitate the in vivo fractional synthesis rate (FSR) and absolute synthesis rate (ASR) of imTGs. However, the extramyocellular TG (emTG) pool, unless precisely excised, contaminates the imTG pool, diluting the imTG-bound tracer enrichment and leading to underestimation of FSR. Because of the difficulty of excising the emTGs precisely, it would be advantageous to be able to calculate the imTG synthesis rate without dissecting the emTGs from each sample. Here, we tested the hypothesis that the ASR of total TGs (tTGs), a combination of imTGs and emTGs, calculated as “FSR × tTG pool,” reasonably represents the imTG synthesis. Muscle lipid parameters were measured in nine healthy women at 90 and 170 min after the start of [(13)C(16)]palmitate infusion. While the measurements of tTG content, enrichment, and FSR did not correlate (P > 0.05), those of the tTG ASR were significantly correlated (r = 0.947, P < 0.05). These results demonstrate that when imTGs and emTGs are pooled, the resulting underestimation of imTG FSR is balanced by the overestimation of the imTG content. We conclude that imTG metabolism is reflected by the measurement of the tTG ASR.

Author(s): Chondronikola, Maria; Magkos, Faidon; Yoshino, Jun; Okunade, Adewole L; Patterson, Bruce W; Muehlbauer, Michael J; Newgard, Christopher B; Klein, Samuel | Abstract: OBJECTIVE:Lactate is an intermediate of glucose metabolism that has been implicated in the pathogenesis of insulin resistance. This study evaluated the relationship between glucose kinetics and plasma lactate concentration ([LAC]) before and after manipulating insulin sensitivity by progressive weight loss. METHODS:Forty people with obesity (BMI = 37.9 ± 4.3 kg/m2 ) were randomized to weight maintenance (n = 14) or weight loss (n = 19). Subjects were studied before and after 6 months of weight maintenance and before and after 5%, 11%, and 16% weight loss. A hyperinsulinemic-euglycemic clamp procedure in conjunction with [6,6-2 H2 ]glucose tracer infusion was used to assess glucose kinetics. RESULTS:At baseline, fasting [LAC] correlated positively with endogenous glucose production rate (r = 0.532; P = 0.001) and negatively with insulin sensitivity, assessed as the insulin-stimulated glucose disposal (r = -0.361; P = 0.04). Progressive (5% through 16%) weight loss caused a progressive decrease in fasting [LAC], and the decrease in fasting [LAC] after 5% weight loss was correlated with the decrease in endogenous glucose production (r = 0.654; P = 0.002) and the increase in insulin sensitivity (r = -0.595; P = 0.007). CONCLUSIONS:This study demonstrates the interrelationships among weight loss, hepatic and muscle glucose kinetics, insulin sensitivity, and [LAC], and it suggests that [LAC] can serve as an additional biomarker of glucose-related insulin resistance.

Brown adipose tissue (BAT) is a recently rediscovered tissue in people that has shown promise as a potential therapeutic target against obesity and its metabolic abnormalities. Reliable non-invasive assessment of BAT volume and activity is critical to allow its importance in metabolic control to be evaluated. Positron emission tomography/computed tomography (PET/CT) in combination with 2-deoxy-2-[18 F]fluoroglucose administration is currently the most frequently used and most established method for the detection and quantification of activated BAT in humans. However, it involves radiation exposure and can detect activated (e.g. after cold exposure), but not quiescent, BAT. Several alternative methods that overcome some of these limitations have been developed including different PET approaches, single-photon emission imaging, CT, magnetic resonance based approaches, contrast-enhanced ultrasound, near infrared spectroscopy, and temperature assessment of fat depots containing brown adipocytes. The purpose of this review is to summarize and critically evaluate the currently available methods that non-invasively probe various aspects of BAT biology in order to assess BAT volume and/or metabolism. Although several of these methods show promise for the non-invasive assessment of BAT volume and function, further research is needed to optimize them to enable an accurate, reproducible and practical means for the assessment of human BAT content and its metabolic function.

Objective Brown adipose tissue (BAT) has been proposed as a potential therapeutic target against obesity and its related metabolic conditions. Data from studies in rodents support a cross talk between BAT and other distal tissues. The relation between BAT and peptide hormones secreted from the gastrointestinal system (GI) and involved in appetite regulation is not known in humans. Design We studied 18 men during thermoneutral conditions and mild non-shivering cold exposure (CE). Methods 2-Deoxy-2-(18F)fluoro-d-glucose positron emission tomography-computed tomography scans were conducted after mild cold to measure BAT volume. Fasting serum concentration of GI-secreted peptides and peptides involved in appetite regulation were measured during thermoneutral conditions and mild CE. Results During thermoneutral conditions, BAT volume was associated with lower serum concentration of leptin (P = 0.006), gastric inhibitory polypeptide (P = 0.016) and glucagon (P = 0.048) after adjusting for age and body fat percent. CE significantly decreased serum leptin (P = 0.004) and glucagon concentration (P = 0.020), while cold-induced BAT activation was significantly associated with lower serum ghrelin concentration (P = 0.029). Conclusions BAT is associated with systemic concentrations of GI-secreted peptides and peptides involved in appetite regulation, suggesting a potential cross talk between BAT and the enteropancreatic axis. Further studies are needed to elucidate the potential link of BAT with the postprandial levels of appetite-regulating peptides and the putative role of BAT in appetite regulation in humans.

Lifestyle (diet and physical activity) may increase asthma risk, but evidence in this area is lacking. The aims of the present study were to calculate an obesity-preventive lifestyle score comprising of eating and physical activity behaviors and investigate the overall effect of lifestyle on asthma in children.A cross-sectional case-control study was carried out in 514 children (217 asthma cases and 297 healthy controls). Data were collected on medical history, anthropometry, dietary intake, and physical activity. We constructed an overweight/obesity-preventive score (OPLS) using study-specific quartile rankings for nine target lifestyle behaviors that were either favorable or unfavorable in preventing obesity (i.e., screen time was an unfavorable lifestyle behavior). The score was developed using the recommendations of the Expert Committee of American Academy of Pediatrics. Score values ranged from 0-18 points; the higher the score, the more protective against high body weight.The OPLS was negatively associated with obesity indices (BMI, waist circumference, and hip circumference), (p 0.05). Control children had a higher score when compared to asthma cases (9.3 ± 2.7 vs. 8.6 ± 2.9, p = 0.007). A high OPLS was protective against physician-diagnosed asthma (OR 0.92; 95% CI 0.86-0.98, p = 0.014), adjusted for several confounders. The OPLS was no longer protective after adjustment for BMI.Higher adherence to an obesity-preventive lifestyle score-consistent with several behaviors for the prevention of childhood overweight/obesity-is negatively associated with obesity indices and lowers the odds for asthma in children. Lifestyle behaviors that contribute to a higher body weight may contribute to the obesity-asthma link. These findings are hypothesis-generating and warrant further investigation in prospective intervention studies.

Nicotinamide adenine dinucleotide (NAD(+)) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD(+) metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD(+) biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD(+)–SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD(+) synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD(+) biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

Brown adipose tissue (BAT) plays an important role in mammalian thermoregulation. The component of BAT mitochondria that permits this function is the inner membrane carrier protein uncoupling protein 1 (UCP1). To the best of our knowledge, no studies have directly quantified UCP1 function in human BAT. Further, whether human and rodent BAT have comparable thermogenic function remains unknown. We employed high-resolution respirometry to determine the respiratory capacity, coupling control, and, most importantly, UCP1 function of human supraclavicular BAT and rodent interscapular BAT. Human BAT was sensitive to the purine nucleotide GDP, providing the first direct evidence that human BATmitochondria have thermogenically functional UCP1. Further, our data demonstrate that human and rodent BAT have similar UCP1 function per mitochondrion. These data indicate that human and rodent BAT are qualitatively similar in terms of UCP1 function.

Acute alterations in skeletal muscle protein metabolism are a well-established event associated with the stress response to burns. Nevertheless, the long-lasting effects of burn injury on skeletal muscle protein turnover are incompletely understood. This study was undertaken to investigate fractional synthesis (FSR) and breakdown (FBR) rates of protein in skeletal muscle of pediatric burn patients (n = 42,30% total body surface area burns) for up to 1 year after injury. Skeletal muscle protein kinetics were measured in the post-prandial state following bolus injections of C6 and N phenylalanine stable isotopes. Plasma and muscle phenylalanine enrichments were quantified using gas chromatography-mass spectrometry. We found that the FSR in burn patients was 2- to 3-fold higher than values from healthy men previously reported in the literature (P ≤ 0.05). The FBR was 4- to 6-fold higher than healthy values (P 0.01). Therefore, net protein balance was lower in burn patients compared with healthy men from 2 weeks to 12 months post-injury (P 0.05). These findings show that skeletal muscle protein turnover stays elevated for up to 1 year after burn, an effect attributable to simultaneous increases in FBR and FSR. Muscle FBR exceeds FSR during this time, producing a persistent negative net protein balance, even in the post-prandial state, which likely contributes to the prolonged cachexia seen in burned victims.

Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a small number of studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergström needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

Brown adipose tissue (BAT) has attracted significant interest as a potential target tissue against obesity and its associated metabolic perturbations. The purpose of this chapter is to provide an overview of some of the methodological approaches that can be used to identify and quantify BAT in people. Specifically, we will provide a step-by-step description of the following procedures: quantification of BAT in vivo using positron emission tomography-computed tomography (PET/CT) with 2-deoxy-2-[

Brown adipose tissue (BAT) has attracted significant interest as a potential target tissue against obesity and its associated metabolic perturbations. The purpose of this chapter is to provide an overview of some of the methodological approaches that can be used to identify and quantify BAT in people. Specifically, we will provide a step-by-step description of the following procedures: quantification of BAT in vivo using positron emission tomography-computed tomography (PET/CT) with 2-deoxy-2-[18F]fluoroglucose (18F-FDG) as a tracer, mitochondrial respiration, and uncoupling protein 1 (UCP1) gene and protein expression.

The recent discovery of functional brown adipose tissue (BAT) in adults has stimulated intense interest for its therapeutic potential against obesity and its related metabolic conditions. Although rodent studies support the importance of brown and beige adipocytes in metabolic health, a smaller number of clinical investigations have examined their physiological significance in people. This chapter provides a critical overview of the published research regarding the metabolic role of BAT and the beiging of white adipose tissue (WAT) in people. In summary, the current available evidence supports the physiological relevance of human BAT in energy, glucose and lipid metabolism. The ability of human WAT to undergo beiging has only recently been demonstrated in patients with severe burn trauma, while its metabolic role remains currently unknown. Future research is needed to gain deeper understanding of the regulating mechanisms and metabolic role of brown and beige adipocytes in health and disease.

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.

Elevated metabolic rate is a hallmark of the stress response to severe burn injury. This response is mediated in part by adrenergic stress and is responsive to changes in ambient temperature. We hypothesize that uncoupling of oxidative phosphorylation in skeletal muscle mitochondria contributes to increased metabolic rate in burn survivors. Here, we determined skeletal muscle mitochondrial function in healthy and severely burned adults. Indirect calorimetry was used to estimate metabolic rate in burn patients. Quadriceps muscle biopsies were collected on two separate occasions (11 ± 5 and 21 ± 8 days postinjury) from six severely burned adults (68 ± 19% of total body surface area burned) and 12 healthy adults. Leak, coupled, and uncoupled mitochondrial respiration was determined in permeabilized myofiber bundles. Metabolic rate was significantly greater than predicted values for burn patients at both time points ( P < 0.05). Skeletal muscle oxidative capacity, citrate synthase activity, a marker of mitochondrial abundance, and mitochondrial sensitivity to oligomycin were all lower in burn patients vs. controls at both time points ( P < 0.05). A greater proportion of maximal mitochondrial respiration was linked to thermogenesis in burn patients compared with controls ( P < 0.05). Increased metabolic rate in severely burned adults is accompanied by derangements in skeletal muscle mitochondrial function. Skeletal muscle mitochondria from burn victims are more uncoupled, indicating greater heat production within skeletal muscle. Our findings suggest that skeletal muscle mitochondrial dysfunction contributes to increased metabolic rate in burn victims.

Evidence supports a significant yet weak association between high-body weight and asthma in children. However, most studies investigating the obesity-asthma link use Body Mass Index (BMI) to evaluate body fatness. The relationship between body fat distribution and asthma remains largely unknown, especially in children. This pediatric case-control investigation examined associations between central obesity/high-body weight and asthma diagnosis.Five-hundred and fourteen children (217 physician diagnosed asthma cases and 297 healthy controls) of 5-11 years were recruited. Height, weight and waist circumference were measured. Asthma symptoms, past medical history, personal lifestyle, socioeconomic status, diet and physical activity history were also collected.A higher proportion of children with asthma were centrally obese [(≥90th waist percentile) 15.2 vs. 9.4%, p0.0001; (≥90th waist-to-height ratio percentile) 39.6 vs. 24.2%, p0.0001)]. Regression analyses revealed that centrally obese children were more likely to have asthma (high-waist circumference (OR = 1.99, 95% CI: 1.07-3.68) and high-waist circumference to height ratio (OR = 2.24, 95% CI: 1.47-3.40), following adjustment for various confounders. Overweight/obese participants (BMI defined) were more likely to be asthmatic [odds ratio (OR) = 1.52, 95% confidence interval (CI): 1.03-2.70)] when compared to controls.Presence of central obesity and high-body weight (at least overweight) as assessed by waist circumference, waist-to-height ratio, and BMI are associated with asthma diagnosis. More studies are needed, especially in children and adolescents, to confirm these findings and better understand how body fat distribution impacts the obesity-asthma relationship.

Burn injury is a dramatic event with acute and chronic consequences including insulin resistance. However, factors associated with insulin resistance have not been previously investigated. The purpose of this study was to identify factors associated with long-term insulin resistance in pediatric burn injury survivors. The study sample consisted of 61 pediatric burn injury survivors 24 to 36 months after the burn injury, who underwent an oral glucose tolerance test. To assess insulin resistance, the authors calculated the area under the curve for glucose and insulin. The diagnostic criteria of the American Diabetes Association were used to define individuals with impaired glucose metabolism. Additional data collected include body composition, anthropometric measurements, burn characteristics, and demographic information. The data were analyzed using multivariate linear regression analysis. Approximately 12% of the patients met the criteria for impaired glucose metabolism. After adjusting for possible confounders, burn size, age, and body fat percentage were associated with the area under the curve for glucose (P < .05 for all). Time postburn and lean mass were inversely associated with the area under the curve for glucose (P < .05 for both). Similarly, older age predicted higher insulin area under the curve. The results indicate that a significant proportion of pediatric injury survivors suffer from glucose abnormalities 24 to 36 months postburn. Burn size, time postburn, age, lean mass, and adiposity are significant predictors of insulin resistance in pediatric burn injury survivors. Clinical evaluation and screening for abnormal glucose metabolism should be emphasized in patients with large burns, older age, and survivors with high body fat.

Asthma and overweight/obesity prevalence are both increasing worldwide. Overweight/obesity has been suggested as a risk factor for developing asthma. The aim of this review is to present and evaluate recent publications that help answer the question: "Is increased body weight (at least overweight status) related to asthma in children?" A systematic review of epidemiologic literature was carried out using the MEDLINE database. Epidemiologic studies on young human subjects (ie, infants, children, and adolescents), published in English during the period 2006-2011 were included. A comprehensive literature search yielded 434 studies for further consideration. Forty-eight studies fulfilled the review's eligibility criteria. Two researchers applied the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies on all identified studies. Current evidence supports a weak yet significant association between high body weight and asthma. New information indicates that central obesity in children increases asthma risk. Also, the link between high body weight and asthma may be stronger in nonallergic asthma. There are mixed results about the importance of sex. Although the nature of the association between overweight/obese status and asthma remains unclear, prospective studies point that high body weight precedes asthma symptoms. These data add weight to the importance of preventing and treating a high body weight against asthma outcomes. Available research in children has not studied adequately the influence of weight change (either gain or loss) on asthma symptoms, an area of clinical importance. Beyond energy control, the role of diet as a possible inflammatory stimulus warrants further investigation. Limited data seem to favor the promotion of breastfeeding in attenuating the overweight/obesity–asthma relationship. Finally, future research should include weight intervention studies assessing various measures of body fat in relation to well-defined asthma outcomes.

Burn injury deformities and obesity have been associated with social integration difficulty and body image dissatisfaction. However, the combined effects of obesity and burn injury on social integration difficulty and body image dissatisfaction are unknown. Adolescent and young adult burn injury survivors were categorized as normal weight (n = 47) or overweight and obese (n = 21). Burn-related and anthropometric information were obtained from patients’ medical records, and validated questionnaires were used to assess the main outcomes and possible confounders. Analysis of covariance and multiple linear regressions were performed to evaluate the objectives of this study. Obese and overweight burn injury survivors did not experience increased body image dissatisfaction (12 ± 4.3 vs 13.1 ± 4.4; P = .57) or social integration difficulty (17.5 ± 6.9 vs 15.5 ± 5.7; P = .16) compared with normal weight burn injury survivors. Weight status was not a significant predictor of social integration difficulty or body image dissatisfaction (P = .19 and P = .24, respectively). However, mobility limitations predicted greater social integration difficulty (P = .005) and body image dissatisfaction (P < .001), whereas higher weight status at burn was a borderline significant predictor of body image dissatisfaction (P = .05). Obese and overweight adolescents and young adults, who sustained major burn injury as children, do not experience greater social integration difficulty and body image dissatisfaction compared with normal weight burn injury survivors. Mobility limitations and higher weight status at burn are likely more important factors affecting the long-term social integration difficulty and body image dissatisfaction of these young people. (J Burn Care Res 2013;34:102–108)

Type 2 diabetes (T2D) is a major worldwide public health concern. Despite a large armamentarium of T2D medications, a large proportion of patients fail to achieve recommended treatment goals for glycemic control. Weight loss has profound beneficial effects on the metabolic abnormalities involved in the pathogenesis of T2D. Accordingly, bariatric surgery, which is the most effective available weight loss therapy, is also the most effective therapy for treating patients with T2D. Surgical procedures that bypass the upper gastrointestinal (UGI) tract are particularly effective in achieving partial and even complete remission of T2D, suggesting that UGI bypass has weight loss-independent effects on glycemic control. Although a number of hypotheses (e.g. a role for multi-organ insulin sensitivity, β-cell function, incretin response, the gut microbiome, bile acid metabolism, intestinal glucose metabolism, and browning of adipose tissue) have been proposed to explain the potential unique effects of UGI tract bypass surgery, none has yet been adequately evaluated to determine therapeutic importance in patients with T2D. Here, we review the efficacy of UGI bypass surgery in treating T2D and the mechanisms that have been proposed to explain its potential weight loss-independent therapeutic effects.

Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients ( n = 14) with burns covering >30% of their total body surface area were studied. Controls ( n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria. In skeletal muscle of burn patients, concurrent activation of mTORC1 signaling and elevation in the fractional synthetic rate paralleled increased levels of proteasomes and elevated fractional breakdown rate. Burn patients had greater levels of oxidative stress markers as well as higher expression of mtUPR-related genes and proteins, suggesting that burns increased mitochondrial stress and protein damage. Indeed, upregulation of cytoprotective genes suggests hypermetabolism-induced oxidative stress postburn. In parallel to mtUPR activation postburn, mitochondrial-specific proteases (LONP1 and CLPP) and mitochondrial translocases (TIM23, TIM17B, and TOM40) were upregulated, suggesting increased mitochondrial protein degradation and transport of preprotein, respectively. Our data demonstrate that proteolysis occurs in both the cytosolic and mitochondrial compartments of skeletal muscle in severely burned patients. Increased mitochondrial protein turnover may be associated with increased protein damage due to hypermetabolism-induced oxidative stress and activation of mtUPR. Our results suggest a novel role for the mitochondria in burn-induced cachexia.

Severe burn injury produces a plethora of metabolic abnormalities which contribute to the prolonged morbidity of burn survivors. The authors have recently demonstrated trans-differentiation of white adipose tissue (WAT) after burn trauma, toward a more thermogenic phenotype. However, the impact of burn injury on subcutaneous WAT (sWAT) morphology in humans is unknown. Here, the authors studied the effect of severe burn injury on the architecture of sWAT. sWAT was collected from 11 severely burned children (11 ± 3 years; 55 ± 16% total BSA burned) and 12 nonburned healthy children (9 ± 3 years). Histology, electron microscopy, immunohistochemistry, and immunofluorescence were performed on fixed adipose tissue sections. sWAT cytokine and collagen concentrations were measured by multiplex assay and sirius/fast green staining method, respectively. sWAT histology demonstrated multiple fat droplets, significantly (P < .05) reduced mean cell size (104 ± 6 vs 68 ± 3 μm) and higher collagen content (7 ± 0.8 vs 4 ± 0.4) in burn patients. sWAT from burn victims stained positive for CD68 suggesting infiltration of macrophages. Furthermore, electron microscopic analysis showed multiple fat droplets and greater mitochondrial abundance in sWAT of burn survivors. In agreement with this, mitochondrial respiratory capacity in the leak and coupled state increased by 100% in sWAT of burned children from 1 to 3 weeks postinjury. The cytokines IL-6, IL-8, IL-13, IL-1a, IL-1b, MCP-1, and TNF-α were all significantly greater in the sWAT of burned children versus healthy children (P < .05). Furthermore, IL-6, IL-8, IL1-a, IL-1b, and TNF-α significantly increased after injury in sWAT of burned children (P < .05). This study provides detailed evidence of morphological and functional changes in sWAT of burn survivors which was associated with tissue inflammation. A better understanding of morphological and functional changes in sWAT will help discern the mechanisms underlying hypermetabolism in burned patients.

Summary Background Circulating acyl-carnitines (acyl-CNTs) are associated with insulin resistance (IR) and type 2 diabetes (T2D) in both rodents and humans. However, the mechanisms whereby circulating acyl-CNTs are increased in these conditions and their role in whole-body metabolism remains unknown. The purpose of this study was to determine if, in humans, blood cells contribute in production of circulating acyl-CNTs and associate with whole-body fat metabolism. Methods and results Eight non-diabetic healthy women (age: 47 ± 19 y; BMI: 26 ± 1 kg·m −2 ) underwent stable isotope tracer infusion and hyperinsulinemic-euglycemic clamp study to determine in vivo whole-body fatty acid flux and insulin sensitivity. Blood samples collected at baseline (0 min) and after 3 h of clamp were used to determine the synthesis rate of palmitoyl-carnitine (palmitoyl-CNT) in vitro . The fractional synthesis rate of palmitoyl-CNT was significantly higher during hyperinsulinemia (0.788 ± 0.084 vs . 0.318 ± 0.012%·hr −1 , p = 0.001); however, the absolute synthesis rate (ASR) did not differ between the periods ( p = 0.809) due to ∼30% decrease in blood palmitoyl-CNT concentration ( p = 0.189) during hyperinsulinemia. The ASR of palmitoyl-CNT significantly correlated with the concentration of acyl-CNTs in basal ( r = 0.992, p r = 0.919, p = 0.001) periods; and the basal ASR significantly correlated with plasma palmitate oxidation ( r = 0.764, p = 0.027). Conclusion In women, blood cells contribute to plasma acyl-CNT levels and the acyl-CNT production is linked to plasma palmitate oxidation, a marker of whole-body fat metabolism. Future studies are needed to confirm the role of blood cells in acyl-CNT and lipid metabolism under different physiological (i.e., in response to meal) and pathological (i.e., hyperlipidemia, IR and T2D) conditions.

Brown adipose tissue (BAT) plays an important role in thermoregulation in rodents. Its role in temperature homeostasis in people is less studied. To this end, we recruited 18 men [8 individuals with no/minimal BAT activity (BAT-) and 10 with pronounced BAT activity (BAT+)]. Each volunteer participated in a 6 h, individualized, non-shivering cold exposure protocol. BAT was quantified using positron emission tomography/computed tomography. Body core and skin temperatures were measured using a telemetric pill and wireless thermistors, respectively. Core body temperature decreased during cold exposure in the BAT- group only (-0.34oC, 95% CI: -0.6 to -0.1, p = 0.03), while the cold-induced change in core temperature was significantly different between BAT+ and BAT- individuals (BAT+ vs. BAT-, 0.43oC, 95% CI: 0.20 to 0.65, p = 0.0014). BAT volume was associated with the cold-induced change in core temperature (p = 0.01) even after adjustment for age and adiposity. Compared to the BAT- group, BAT+ individuals tolerated a lower ambient temperature (BAT-: 20.6± 0.3oC vs. BAT+: 19.8 ± 0.3oC, p=0.035) without shivering. The cold-induced change in core temperature (r = 0.79, p = 0.001) and supraclavicular temperature (r = 0.58, p = 0.014) correlated with BAT volume, suggesting that these non-invasive measures can be potentially used as surrogate markers of BAT when other methods to detect BAT are not available or their use is not warranted. These results demonstrate a physiologically significant role for BAT in thermoregulation in people. This trial has been registered with Clinaltrials.gov: NCT01791114 https://clinicaltrials.gov/ct2/show/NCT01791114)

SummarySince the presence of brown adipose tissue (BAT) was confirmed in adult humans, BAT has become a therapeutic target for obesity and insulin resistance. We examined whether human subcutaneous white adipose tissue (sWAT) can adopt a BAT-like phenotype using a clinical model of prolonged and severe adrenergic stress. sWAT samples were collected from severely burned and healthy individuals. A subset of burn victims were prospectively followed during their acute hospitalization. Browning of sWAT was determined by the presence of multilocular adipocytes, uncoupling protein 1 (UCP1), and increased mitochondrial density and respiratory capacity. Multilocular UCP1-positive adipocytes were found in sWAT samples from burn patients. UCP1 mRNA, mitochondrial density, and leak respiratory capacity in sWAT increased after burn trauma. Our data demonstrate that human sWAT can transform from an energy-storing to an energy-dissipating tissue, which opens new research avenues in our quest to prevent and treat obesity and its metabolic complications.

Chronic adrenergic stress results in the browning of subcutaneous white adipose tissue (WAT), i.e. increased oxidative capacity and uncoupling protein 1 (UCP1) expression in rodents and possibly in...

©2005 Nature America, Inc. All rights reserved. Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.

Recent studies suggest that brown adipose tissue (BAT) plays a role in energy and glucose metabolism in humans. However, the physiological significance of human BAT in lipid metabolism remains unknown. We studied 16 overweight/obese men during prolonged, non-shivering cold and thermoneutral conditions using stable isotopic tracer methodologies in conjunction with hyperinsulinemic-euglycemic clamps and BAT and white adipose tissue (WAT) biopsies. BAT volume was significantly associated with increased whole-body lipolysis, triglyceride-free fatty acid (FFA) cycling, FFA oxidation, and adipose tissue insulin sensitivity. Functional analysis of BAT and WAT demonstrated the greater thermogenic capacity of BAT compared to WAT, while molecular analysis revealed a cold-induced upregulation of genes involved in lipid metabolism only in BAT. The accelerated mobilization and oxidation of lipids upon BAT activation supports a putative role for BAT in the regulation of lipid metabolism in humans.