François Haman

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.

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.

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.”

Pathways for metabolic fuels and oxygen in high performance fish

Abstract This paper gives an overview of oxidative fuel metabolism in swimming fish, and known or potential modifications occurring in high-performance species are explored. Carbohydrate catabolism is the only source of ATP for sprint swimming where locomotory muscles operate as closed systems. In contrast, this substrate only plays a very minor role in prolonged swimming. Glucose fluxes have been measured in vivo in several species, but mainly at rest and with somewhat questionable methodologies. High-performance species may be able to sustain higher maximal glucose fluxes that their sedentary counterparts by: a) upregulating gluconeogenesis, b) increasing glucose transporter density or V max of individual transporters, c) storing larger amounts of glycogen in liver and muscle, and d) increasing muscle hexokinase activity. Even though lipids represent a much more important source of energy for sustained swimming, their fluxes have not been measured in vivo , even at rest, probably because of their diversity and complex chemistry. Except for elasmobranchs who do not possess plasma proteins for lipid transport, high-performance fish should be able to sustain high maximal lipid fluxes by: a) elevating lipolytic capacity, b) increasing rates of circulatory lipid transport through modified plasma proteins, c) augmenting intramuscular lipid reserves, and d) upregulating capacity for lipid oxidation in locomotory muscle mitochondria. The quantitative assessment of amino acid oxidation in swimming fish is a priority for future research because protein is probably a dominant metabolic fuel in most swimming fish. Finally, we predict that high-performance species should use proportionately more proteins/lipids and less carbohydrates than low-aerobic fish. Also, and similarly to endurance-adapted mammals, high-performance fish should increase their relative reliance on intramuscular fuel reserves and decrease their relative use of circulatory fuels.

Partitioning oxidative fuels during cold exposure in humans: muscle glycogen becomes dominant as shivering intensifies

The effects of changes in shivering intensity on the relative contributions of plasma glucose, muscle glycogen, lipids and proteins to total heat production are unclear in humans. The goals of this study were: (1) to determine whether plasma glucose starts playing a more prominent role as shivering intensifies, (2) to quantify overall changes in fuel use in relation to the severity of cold exposure, and (3) to establish whether the fuel selection pattern of shivering is different from the classic fuel selection pattern of exercise. Using a combination of indirect calorimetry and stable isotope methodology, fuel metabolism was monitored in non‐acclimatized adult men exposed for 90 mins to 10°C (low‐intensity shivering (L)) or 5°C (moderate‐intensity shivering (M)). Results show that plasma glucose oxidation is strongly stimulated by moderate shivering (+122% from L to M), but the relative contribution of this pathway to total heat generation always remains minor (< 15% of total heat production). Instead, muscle glycogen is responsible for most of the increase in heat production between L and M. By itself, the increase in CHO oxidation is responsible for the 100 W increase in metabolic rate observed between L and M, because rates of lipid and protein oxidation remain constant. This high reliance on CHO is not compatible with the well known fuel selection pattern of exercise, when considering the relatively low metabolic rates elicited by shivering (∼30% for M). We conclude that shivering and exercise of similar energy requirements appear to be supported by different fuel mixtures. Investigating the physiological mechanisms underlying why a muscle producing only heat (shivering), or significant movement (exercise), shows a different pattern of fuel selection at the same power output strikes us as a fascinating area for future research.

Fuel selection during intense shivering in humans: EMG pattern reflects carbohydrate oxidation

The thermogenic response of humans depends critically on the coordination of muscle fibre recruitment and oxidative fuel metabolism. The primary goal of this study was to determine whether the electromyographic (EMG) pattern of muscle recruitment could provide metabolic information on oxidative fuel selection during high‐intensity shivering. EMG activity (of 8 large muscles) and fuel metabolism were monitored simultaneously in non‐acclimatized adult men during high‐intensity shivering. Even though acute cold exposure elicited similar changes in metabolic rate among subjects, lipid and carbohydrate use was very different. Depending on the subject, the cold‐induced increase in carbohydrate (CHO) oxidation ranged between 2‐ and 8‐fold, with CHO accounting for 33–78% of total heat production , and lipids for 14–60%. This high variability in fuel selection was primarily explained by differences in ‘burst shivering’ rate, indicating that the recruitment of type II fibres plays a key role in orchestrating fuel selection. This study is the first to show that the pattern of muscle recruitment can provide quantitative information on energy metabolism. Future work should focus on the study of shivering bursts that may provide essential clues on what limits human survival in the cold.

Effects of hypoxia and low temperature on substrate fluxes in fish: plasma metabolite concentrations are misleading

Oxygen levels and temperature can fluctuate rapidly in aquatic environments. Even though the effects of environmental stresses on fish metabolism have been studied extensively, information on fuel kinetics is extremely limited because it relies almost exclusively on changes in substrate concentrations. The turnover rate of nonesterified fatty acids (NEFA) has never been measured in fish. Therefore, our goal was to quantify glucose and NEFA fluxes in rainbow trout acutely exposed to severe hypoxia (25% O2 saturation) or low temperature (6°C for fish acclimated to 15°C) by performing continuous infusions of 6-[3H]glucose and 1-[14C]palmitate in vivo. Results show that hypoxia causes a 53% decrease in NEFA turnover rate, together with a transient increase in hepatic glucose production, whereas a rapid drop in temperature induces equivalent declines in glucose, NEFA, and oxygen fluxes [temperature coefficient ≅ 2]. More importantly, kinetic changes in glucose and NEFA fluxes are not accompanied by interpretable changes in the plasma concentrations of these metabolites. Thus using concentration changes to draw conclusions about fluxes must be avoided.

Energetics of a long-distance migrant shorebird (Philomachus pugnax) during cold exposure and running.

SUMMARY The metabolic consequences of cold exposure and exercise are not well characterized in birds. Ruff sandpipers Philomachus pugnax are migrant shorebirds traveling between Africa and Siberia for up to 30 000 km annually. Our goal was to quantify the fuel selection pattern of these remarkable athletes during shivering and terrestrial locomotion. We used indirect calorimetry and nitrogen excretion analysis to measure their rates of lipid, carbohydrate and protein oxidation at different temperatures (22, 15, 10 or 5°C) and different treadmill speeds (15, 20, 25, 30, 35 or 40 m min–1). Results show that lipid oxidation supplies nearly all the energy necessary to support shivering and running, and that the pattern of oxidative fuel selection is independent of shivering or running intensity. During shivering, total ATP production is unequally shared between lipids (82%), carbohydrates (12%) and proteins (6%). During running, lipids remain the dominant substrate (66%), with carbohydrates (29%) and proteins (5%) playing more minor roles. The prevailing use of lipids during intense shivering and high-speed running is not consistent with the fuel selection pattern observed in exercising and cold-exposed mammals. The exact mechanisms allowing birds to use lipids at extremely high rates are still largely unexplored, and quantifying the relative importance of different fuels during long-distance flight remains a major challenge for future research.

Obesity and type 2 diabetes in Northern Canada's remote First Nations communities: the dietary dilemma.

First Nations populations in Northwestern Ontario have undergone profound dietary and lifestyle transformations in less than 50 years, which have contributed to the alarming rise in obesity and obesity-related diseases, in particular type 2 diabetes mellitus. Even though the genetic background of First Nations peoples differs from that of the Caucasians, genetics alone cannot explain such a high prevalence in obesity and type 2 diabetes. Modifications in lifestyle and diet are major contributors for the high prevalence of chronic diseases. What remains constant in the literature is the persistent view that locally harvested and prepared foods are of tremendous value to First Nations peoples providing important health and cultural benefits that are increasingly being undermined by western-based food habits. However, the complexities of maintaining a traditional diet require a multifaceted approach, which acknowledges the relationship between benefits, risks and viability that cannot be achieved using purely conventional medical and biological approaches. This brief review explores the biological predispositions and potential environmental factors that contribute to the development of the high incidence of obesity and obesity-related diseases in First Nations communities in Northern Canada. It also highlights some of the complexities of establishing exact physiological causes and providing effective solutions.