In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24°C [month 1] → 19°C [month 2] → 24°C [month 3] → 27°C [month 4]) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits.

Energy metabolism is one of the most recognized targets of thyroid hormone action, which indeed plays a critical role in modulating energy expenditure in all of its components. This is because thyroid hormone receptors are ubiquitous, and thyroid hormones interact and influence most metabolic pathways in virtually all systems throughout the entire life of the organism. The pleiotropic actions of thyroid hormone are the results of interaction between the local availability of T3 and the signal transduction machinery, which confer in physiologic conditions time and tissue specificity of the hormonal signal despite negligible variations in circulating levels. Historically, the measurement of energy expenditure has been used as the gold standard for the clinical assessment of the hormonal action until the advent of the immunoassays for TSH and thyroid hormone, which have since been used as proxy for measurement of thyroid hormone action. Although the clinical correlates between thyroid hormone action and energy expenditure in cases of extreme dysfunction (florid hyperthyroidism or hypothyroidism) are well recognized, there is still controversy on the effects of moderate, subclinical thyroid dysfunction on energy expenditure and, ultimately, on body weight trajectory. Moreover, little information is available on the effects of thyroid hormone replacement therapy on energy expenditure. This mini review is aimed to define the clinical relevance of thyroid hormone action in normal physiology and functional disorders, as well the effects of thyroid hormone therapy on energy expenditure and the effects of changes in energy status on the thyroid hormone axis.

Background: Thyroid hormones are important determinants of energy expenditure, and in rodents, adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction. Methods: To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, 47 subjects with a body mass index (BMI) of 25–45 kg/m ² were enrolled in a longitudinal intervention study; 30 nonoverweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a 12-month individualized dietary intervention aimed at achieving a 5–10% weight loss. Results: The intervention resulted in a 6.3±0.9 kg (6.5±1.0%) weight loss. At baseline, thyrotropin (TSH) and T3 concentrations correlated significantly with fat mass ( R =0.257, p =0.024 and R =0.318, p =0.005, respectively). After weight loss, T3 decreased significantly (from 112.7±3.1 to 101.8±2.6 ng/dL, p <0.001) in the absence of significant changes in TSH or free T4 (fT4). The decrease in serum T3 correlated with the decrease in weight ( R =0.294, p 5% body weight. Conclusions: T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the prohormone T4 into its hormonally active metabolite T3 is at least in part responsible for the observed changes in thyroid hormone homeostasis.

Thyroid hormone (TH) has diverse effects on mitochondria and energy expenditure (EE), generating great interest and research effort into understanding and harnessing these actions for the amelioration and treatment of metabolic disorders, such as obesity and diabetes. Direct effects on ATP utilization are a result of TH’s actions on metabolic cycles and increased cell membrane ion permeability. However, the majority of TH induced EE is thought to be a result of indirect effects, which, in turn, increase capacity for EE. This review discusses the direct actions of TH on EE, and places special emphasis on the indirect actions of TH, which include mitochondrial biogenesis and reduced metabolic efficiency through mitochondrial uncoupling mechanisms. TH analogs and the metabolic actions of T2 are also discussed in the context of targeted modulation of EE. Finally, clinical correlates of TH actions on metabolism are briefly presented.

Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype – “beige” or “brite” adipose tissue – in a process referred to as “browning.” While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots – white, brown, and beige – to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement: Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials.