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Energy dissipation through the promotion of brown adipose tissue (BAT) or browning of white adipose tissue has recently evolved as novel promising concept in the fight against metabolic disease. New evidence suggests that hormones can contribute to the thermogenic programming of adipocytes through paracrine or endocrine actions. Recent studies in rodents identified parathyroid hormone (PTH) and PTH-related peptide as mediators of energy wasting in cachexia models due to adipocyte browning. However, the effects of PTH on human adipocyte thermogenesis and metabolic activity are unknown. Here we isolated subcutaneous white adipocyte precursor cells (APCs) from human donors followed by stimulation with recombinant PTH. Our data show that acute and chronic PTH administration in primary in vitro differentiated human subcutaneous adipocytes induces a molecular thermogenic program with increased mitochondrial activity and oxidative respiratory capacity. PTH also enhances hormone sensitive lipase activity and lipolysis in human adipocytes which may contribute to the observed thermogenic effects. In summary, we demonstrate here that PTH is a novel mediator of human adipocyte browning, suggesting a hitherto unknown endocrine axis between the parathyroid gland and adipose tissue in humans.

Context Mounting evidence suggests beneficial effects of brown adipose tissue (BAT) activation on glucose and lipid metabolism in humans. It is unclear whether cold-induced BAT activation affects not only insulin sensitivity but also insulin secretion. Likewise, the role in clearing circulating fatty acids (FAs) has not been fully explored. Objective Exploring the effects of cold-induced BAT activation on insulin sensitivity and secretion, as well as on plasma FA profiles. Design Fifteen healthy men participated in a cross-balanced repeated within-subject study with two experimental conditions. Subjects were exposed to thermoneutrality (22°C) and to moderate cold (18.06°C, shivering excluded) by use of a water-perfused whole body suit. Cold-induced BAT activation was quantified by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography in a subset of volunteers. A Botnia clamp procedure was applied to determine pancreatic first phase insulin response (FPIR) and insulin sensitivity. Hormones and metabolites, including 26 specific plasma FAs, were sampled throughout the experiment. Results Cold exposure induced BAT activity. Plasma noradrenaline and dopamine concentrations increased in response to cold. Peripheral glucose uptake and insulin sensitivity significantly improved by ∼20%, whereas FPIR remained stable. Lignoceric acid (C24:0) concentrations increased, whereas levels of eicosanoic acid (C20:1n9), nervonic acid (C24:1n9), and behenic acid (C22:0) decreased. Conclusions Cold-exposure induces sympathetic nervous system activity and BAT metabolism in humans, resulting in improved glucose metabolism without affecting pancreatic insulin secretion. In addition, BAT activation is associated with altered circulating concentrations of distinct FAs. These data support the concept that human BAT metabolism significantly contributes to whole body glucose and lipid utilization in a coordinated manner.