Signaling Pathways Regulating Thermogenesis

Abstract

Obesity, an excess accumulation of white adipose tissue (WAT), has become a global epidemic and is associated with complex diseases, such as type 2 diabetes and cardiovascular diseases. Presently, there are no safe and effective therapeutic agents to treat obesity. In contrast to white adipocytes that store energy as triglycerides in unilocular lipid droplet, brown and brown-like or beige adipocytes utilize fatty acids (FAs) and glucose at a high rate mainly by uncoupling protein 1 (UCP1) action to uncouple mitochondrial proton gradient from ATP synthesis, dissipating energy as heat. Recent studies on the presence of brown or brown-like adipocytes in adult humans have revealed their potential as therapeutic targets in combating obesity. Classically, the main signaling pathway known to activate thermogenesis in adipocytes is β3-adrenergic signaling, which is activated by norepinephrine in response to cold, leading to activation of the thermogenic program and browning. In addition to the β3-adrenergic signaling, numerous other hormones and secreted factors have been reported to affect thermogenesis. In this review, we discuss several major pathways, β3-adrenergic, insulin/IGF1, thyroid hormone and TGFβ family, which regulate thermogenesis and browning of WAT.

Integrated application of metabolomics and RNA‐seq reveals thermogenic regulation in goat brown adipose tissues

“…Then β-adrenergic/p38 MAPK signaling is activated and phosphorylates several transcription factors (ATF2, CREB, and PGC1α) to trigger the thermogenic program and browning of WAT. 13 It has been proved in rodents that brown adipocytes are derived from Myf5 + mesenchymal precursors using in vivo lineage tracing. 14 And Myf5 + progenitor cells into the adipogenic program are determined by the PR domain zinc finger protein 16 (PRDM16), which is essential for the switch between brown adipocytes and myocytes.…”

Defective brown adipose tissue thermogenesis and impaired glucose metabolism in mice lacking Letmd1

“…b3-Adrenergic signaling is widely considered to be a dominant pathway governing fat thermogenesis in the context of cold exposure. Elevated levels of cAMP that result from b3-receptor stimulation promote activation of protein kinase A (PKA), which in turn targets downstream molecules such as p38 mitogen-activated protein kinase (MAPK), CREB, and hormone sensitive lipase (HSL) (Mayr and Montminy, 2001;Tabuchi and Sul, 2021). The induction of Lemd1 in cultured mouse adipocytes by the b3-adrenergic agonist CL315,243 is blocked by a CREB inhibitor (Figures 1K and 1L), and the Letmd1 level in human adipocytes is increased by forskolin, a stimulator of cAMP signaling (Figure 1H), pointing to a key role for the cAMP-PKA signaling pathway in regulating Letmd1 gene expression.…”

The COVID-19 "Bad Tryp" Syndrome: NAD/NADH+, Tryptophan Phenylalanine Metabolism and Thermogenesis like Hecatomb - The Hypothesis of Pathophysiology Based on a Compared COVID-19 and Yellow Fever Inflammatory Skeleton

“…5-HT reduces cAMP levels in iBAT, lowers HSL activation, and reduces the expression of uncoupling protein 1 (UCP1), the mitochondrial protein responsible for thermogenesis). Peripheral 5-HT augments obesity by suppressing the "browning" of white fat, reducing UCP1 in BAT, and suppressing the secretion and expression of metabolically beneficial adiponectin [124][125][126].…”