Sébastien M. Labbé

Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

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.

Increased Brown Adipose Tissue Oxidative Capacity in Cold-Acclimated Humans

Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes, which may have important pathological and therapeutic implications. Although many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: Our objective was to determine whether 4 weeks of daily cold exposure could increase both the volume of metabolically active BAT and its oxidative capacity. Design: Six nonacclimated men were exposed to 10°C for 2 hours daily for 4 weeks (5 d/wk), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with [11C]acetate and [18F]fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake, and volume before and after 4 weeks of cold acclimation were examined under controlled acute cold-exposure conditions. Results: The 4-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66 ± 30 to 95 ± 28 mL, P < .05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725 ± 0.300 to 1.591 ± 0.326 mL·s−1, P < .05). Shivering intensity was not significantly different before compared with after acclimation (2.1% ± 0.7% vs 2.0% ± 0.5% maximal voluntary contraction, respectively). Fractional glucose uptake in BAT increased after acclimation (from 0.035 ± 0.014 to 0.048 ± 0.012 min−1), and net glucose uptake also trended toward an increase (from 163 ± 60 to 209 ± 50 nmol·g−1·min−1). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis.

Effect of Alipogene Tiparvovec (AAV1-LPLS447X) on Postprandial Chylomicron Metabolism in Lipoprotein Lipase-Deficient Patients

BACKGROUND Lipoprotein lipase-deficient (LPLD) individuals display marked chylomicronemia and hypertriglyceridemia associated with increased pancreatitis risk. The aim of this study was to determine the effect of i.m. administration of an adeno-associated viral vector (AAV1) for expression of LPL(S447X) in muscle (alipogene tiparvovec, AAV1-LPL(S447X)) on postprandial chylomicron metabolism and on nonesterified fatty acid (NEFA) and glycerol metabolism in LPLD individuals. METHODOLOGY In an open-label clinical trial (CT-AMT-011-02), LPLD subjects were administered alipogene tiparvovec at a dose of 1 × 10(12) genome copies per kilogram. Two weeks before and 14 wk after administration, chylomicron metabolism and plasma palmitate and glycerol appearance rates were determined after ingestion of a low-fat meal containing (3)H-palmitate, combined with (continuous) iv infusion of [U-(13)C]palmitate and [1,1,2,3,3-(2)H]glycerol. PRINCIPAL FINDINGS After administration of alipogene tiparvovec, the triglyceride (TG) content of the chylomicron fraction and the chylomicron-TG/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron (3)H level and chylomicron (3)H area under the curve were greatly reduced (by 79 and 93%, 6 and 24 h after the test meal, respectively). There were no significant changes in plasma NEFA and glycerol appearance rates. Plasma glucose, insulin, and C-peptide also did not change. CONCLUSIONS/SIGNIFICANCE Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover.

In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis

The present study was designed to investigate the effects of cold on brown adipose tissue (BAT) energy substrate utilization in vivo using the positron emission tomography tracers [18F]fluorodeoxyglucose (glucose uptake), 14(R,S)‐[18F]fluoro‐6‐thiaheptadecanoic acid [nonesterified fatty acid (NEFA) uptake], and [11C]acetate (oxidative activity). The measurements were performed in rats adapted to 27°C, which were acutely subjected to cold (10°C) for 2 and 6 hours, and in rats chronically adapted to 10°C for 21 days, which were returned to 27°C for 2 and 6 hours. Cold exposure (acutely and chronically) led to increases in BAT oxidative activity, which was accompanied by concomitant increases in glucose and NEFA uptake. The increases were particularly high in cold‐adapted rats and largely readily reduced by the return to a warm environment. The cold‐induced increase in oxidative activity was meaningfully blunted by nicotinic acid, a lipolysis inhibitor, which emphasizes in vivo the key role of intracellular lipid in BAT thermogenesis. The changes in BAT oxidative activity and glucose and NEFA uptakes were paralleled by inductions of genes involved in not only oxidative metabolism but also in energy substrate replenishment (triglyceride and glycogen synthesis). The capacity of BAT for energy substrate replenishment is remarkable.—Labbé, S. M., Caron, A., Bakan, I., Laplante, M., Carpentier, A. C., Lecomte, R., Richard, D. In vivo measurement of energy substrate contribution to cold‐induced brown adipose tissue thermogenesis. FASEB J. 29, 2046‐2058 (2015). www.fasebj.org

Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men

Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized.

Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes

Spontaneous glucose uptake by brown adipose tissue (BAT) is lower in overweight or obese individuals and in diabetes. However, BAT metabolism has not been previously investigated in patients with type 2 diabetes during controlled cold exposure. Using positron emission tomography with 11C-acetate, 18F-fluoro-deoxyglucose (18FDG), and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, BAT oxidative metabolism and perfusion and glucose and nonesterified fatty acid (NEFA) turnover were determined in men with well-controlled type 2 diabetes and age-matched control subjects under experimental cold exposure designed to minimize shivering. Despite smaller volumes of 18FDG-positive BAT and lower glucose uptake per volume of BAT compared with young healthy control subjects, cold-induced oxidative metabolism and NEFA uptake per BAT volume and an increase in total body energy expenditure did not differ in patients with type 2 diabetes or their age-matched control subjects. The reduction in 18FDG-positive BAT volume and BAT glucose clearance were associated with a reduction in BAT radiodensity and perfusion. 18FDG-positive BAT volume and the cold-induced increase in BAT radiodensity were associated with an increase in systemic NEFA turnover. These results show that cold-induced NEFA uptake and oxidative metabolism are not defective in type 2 diabetes despite reduced glucose uptake per BAT volume and BAT “whitening.”

Increased Myocardial Uptake of Dietary Fatty Acids Linked to Cardiac Dysfunction in Glucose-Intolerant Humans

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.

Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography

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)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered (18)FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant (18)FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of (18)FTHA in the distal thoracic duct, reaching a peak at time 240 min. (18)FTHA 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 (18)F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received (18)FTHA 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.

Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats.

This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPARγ expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPARγ remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.