Human Brown Adipose Tissue Plasticity: Hormonal and Environmental Manipulation

Excerpt

Brown adipose tissue (BAT), brown-in-white (“brite”) and “beige” adipocytes share the unique ability of converting chemical energy into heat and play a critical role in the adaptive thermogenesis response promoting nonshivering thermogenesis. Uncoupling Protein-1 (UCP1), which allows the uncoupling of substrate oxidation from phosphorylation of ADP, represents the molecular signature of BAT and beige adipocytes. Until recently, the physiologic role of BAT and beige adipocytes depots was thought to be limited to small mammalians and newborns.

The discovery of BAT in adult humans and the demonstration of the presence of inducible BAT activity in white adipose tissue by beige adipocytes have generated enthusiasm as potential targets for treatment of obesity and other disorders due to sustained positive energy balance. These findings are particularly important since in vitro studies have demonstrated that preadipocytes can be directed toward a common brown phenotype by multiple pathways that, in turn, may be exploited for therapeutic interventions. In adult humans, BAT activity is more evident in deep neck fat depots and, to a lesser degree, in subcutaneous adipose tissue, with a transcriptome signature resembling the rodent beige fat. This observation supports the hypothesis that human BAT activity and capacity can be modulated. To this end, we have directed our translational research program toward the characterization of beige fat in humans and on the effects of hormonal and environmental drivers in the adaptive thermogenesis response. Mild cold exposure, within the temperature range commonly employed in climate-controlled buildings, is sufficient to generate a significant increase in non-shivering thermogenesis driven by BAT and beige adipocyte activation. In turn, adaptive thermogenesis generates a specific hormonal signature and promotes glucose disposal. Chronic exposure to mild cold induces expansion of BAT mass and activity, whereas exposure to warm climate abrogates them. Additionally, the metabolic effects of BAT mass expansion are evident only upon stimulation of BAT activity, indicating that both expansion and activation of BAT are necessary and complementary strategies to pursue. From an experimental standpoint, human preadipocytes represent a viable experimental platform to mechanistically interrogate different pathways that are able to expand and activate browning. Our laboratory has focused on studying FGF-21, and FNDC5/irisin in their capacity to promote the browning process. Compared to a white differentiation medium, the addition of either FGF-21 or FNDC5 results in a reprogramming toward a brown phenotype, as indicated by the display of brown transcriptome signature and, functionally, by the increase in oxygen consumption following catecholamine treatment, indicating an increase in substrate utilization. Collectively, the integration of a detailed assessment of human physiology with mechanistic observations in cell culture systems can provide a unique opportunity to translate observations from experimental models to actionable therapeutic targets.