Endocrine function of human brown adipose tissue and its exercise-induced regulators

Abstract

Since the presence and activity of brown adipose tissue (BAT) was recognized in human adults in 2009, its study has been gaining interest within the scientific community. Researchers aim to identify non-invasive methods to promote BAT activation as well as to determine its metabolic effects on human health. In addition to the thermogenic activity of BAT, its secretory capacity has been evidenced, and is now recognized that BAT is able to release endocrine signaling molecules, the so-called batokines or brown adipokines. These batokines seem to exert beneficial effects on energy homeostasis and promote white adipose tissue (WAT) browning, a process by which white adipocytes acquire a brown-like phenotype. However, most batokines have been only identified in rodents and in vitro models, which is difficult to translate to human physiology. Besides producing endocrine signals, BAT is responsive to many endocrine circulating factors. Studies in mice have suggested that exercise could induce BAT activation and WAT browning, and that this effect may be modulated by the exercise-induced release of endocrine factors, the so-called exerkines. The overall aim of this Doctoral Thesis is to study the endocrine connections of human BAT, by investigating circulating molecules potentially secreted by BAT in response to cold exposure and exercise-induced signals that can regulate BAT metabolism. The Study I of this Doctoral Thesis attempts to identify the effect of a 2-hour individualized cold exposure on the plasma levels of five potential batokines, previously identified in mice (i.e.: CXLC14, GDF14, FGF21, interleukin-6, and BMP8b). The individualized cooling protocol increased the plasma levels of CXCL14, GDF15, FGF21 and interleukin-6 and decreased the plasma levels of BMP8b. Moreover, the cold-induced changes in circulating FGF21 were positively associated with BAT volume, as measured by a static 18F-FDG PET-CT. These results suggest that human BAT might contribute to the circulating pool of FGF21 upon BAT activation. The Study II aims to characterize the acute and chronic effect of resistance and endurance exercise on the concentration of 16 exerkines known to regulate BAT metabolism. An intense and short bout of endurance exercise elevated plasma levels of noradrenaline, lactate, BDNF, interleukin-6, follistatin-like 1 protein, musclin, and FGF21, whereas it decreased the plasma levels of leptin. Resistance exercise acutely increased lactate levels, but not the other 15 analyzed exerkines. On the other hand, a 24-week training program combining resistance and endurance exercise failed to modulate the circulating levels of these exerkines. Only the endurance acute exercise-induced change in plasma lactate levels were positively associated with BAT parameters, suggesting an inter-organ communication between BAT and skeletal muscle. The findings obtained in this Doctoral Thesis contribute to extend the knowledge on human BAT physiology. These findings may be a starting point for future studies aimed at elucidating the cardiometabolic effect of BAT activity in humans and the possible development of therapeutic and preventive strategies against obesity and associated diseases.