Human Brown Adipose Tissue Plasticity: Hormonal and Environmental Manipulation

Abstract

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 F. S. Celi (*) Division of Endocrinology Diabetes and Metabolism, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA e-mail: Francesco.celi@vchuhealth.org 2 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 utilizat...

The novel non‐steroidal MR antagonist finerenone improves metabolic parameters in high‐fat diet‐fed mice and activates brown adipose tissue via AMPK‐ATGL pathway

“…Indeed, a deeper understanding of the molecular mechanisms regulating BAT function may lead to identify novel molecular targets against adipose tissue (AT) disorders and obesity. 24 Notably, healthy humans treated for two weeks with the MR antagonist spironolactone showed activation of BAT (in response to cold stimuli) at the level of cervical, supraclavicular, axillary, and paravertebral fat depots. 25,26 In clinical practice, the use of spironolactone is limited by side effects such as gynecomastia and erectile dysfunction, since it also binds to androgen and progesterone receptors.…”

“…There is a growing interest in studying BAT as a potential therapeutic target in the treatment of obesity since the increase in BAT activity could trigger an increased energy expenditure, potentially improving glucose and lipid profile. Indeed, a deeper understanding of the molecular mechanisms regulating BAT function may lead to identify novel molecular targets against adipose tissue (AT) disorders and obesity 24 . Notably, healthy humans treated for two weeks with the MR antagonist spironolactone showed activation of BAT (in response to cold stimuli) at the level of cervical, supraclavicular, axillary, and paravertebral fat depots 25,26 .…”

Regulatory microRNAs in Brown, Brite and White Adipose Tissue

“…As such, brite AT expresses inducible UCP1 and exhibits a medium density of mitochondria [ 4 , 5 , 6 , 7 ]. The plasticity of WAT and brite AT appears to play a significant role [ 41 ], as bidirectional inter-conversion processes have been documented between WAT and brite AT [ 42 ]. In addition to expressing adipogenic genes ( UCP1 ; Cell death-inducing DNA fragmentation factor-like effector A, CIDEA ; CCAAT/enhancer-binding protein beta, C/EBPB ; and Peroxisome proliferator-activated receptor gamma coactivator 1alpha, PGC1A ), brite adipocytes also express certain brite markers, such as CD137 (4-1BB, or tumor necrosis factor receptor superfamily member 9, TNFRSF9), transmembrane protein 26 (TMEM26), or T-Box transcription factor 1 (TBX1) [ 36 , 43 ].…”

The colors of adipose tissue

“…The same group points out that irisin induces the conversion of human preadipocytes into beige adipocytes, while generating more heat by thermogenesis. 62 Irisin and other signals appear to be responsible for causing adaptive thermogenesis and changing adipose tissue "color shades" in humans; however, this will have to be confirmed in the future. Nevertheless, it is clear that adipose tissue plasticity, its capacity for interconversion, transdifferentiation and "browning" offer an opportunity to modulate energy metabolism.…”

“…For example, a change in room temperature from 24 to 19 and 17 °C increases brown adipose tissue mass, as well as energy expenditure, through an increase in the use of lipids and glucose. 62 Since physical activity and "shivering" simultaneously induce heat and irisin production in muscle tissue, the influence of this hormone on human white adipose tissue "browning" or transdifferentiation has been studied. Investigations are controversial.…”