Recruitment of Thermogenic Fat: Trigger of Fat Burning

Abstract

Brown and beige adipose tissues possess the remarkable capacity to convert energy into heat, which potentially opens novel therapeutic perspectives targeting the epidemic of metabolic syndromes such as obesity and type 2 diabetes. These thermogenic fats implement mitochondrial oxidative phosphorylation and uncouple respiration to catabolize fatty acids and glucose, which leads to an increase in energy expenditure. In particular, beige adipocytes that arise in white adipose tissue display their thermogenic capacity through various noncanonical mechanisms. This review aims to summarize the general overview of thermogenic fat, especially including the UCP1-independent adaptive thermogenesis and the emerging mechanisms of "beiging", which may provide more evidence of targeting thermogenic fat to counteract obesity and other metabolic disorders in humans.

Keywords: UCP1; beiging; brown/beige fat; obesity; thermogenesis.

Figure 1

Canonical non-shivering thermogenesis. In response to cold exposure and overeating, norepinephrine (NE) binds to β3-adrenoceptor (β3-AR), initiating adenosine cyclase-cAMP-protein kinase A (AC-cAMP-PKA) pathway. Subsequently the hormone-sensitive lipase (HSL) on the surface of lipid droplets is phosphorylated and the triglycerides translate into free-fatty-acid (FFA) after hydrolysis, which activates uncoupling protein 1 (UCP1) that inhibited by ATP, as a substrate for the following β-oxidation in the mitochondrial matrix. Additionally, interorgan communication provides more available substrates and fuels from exogenous sources, such as glucose, oxygen, FFA, acylcarnitine, metabolites, which come from the circulation, WAT, liver, and gut microbiome. Figure created using BioRender (https://biorender.com/).

Figure 2

Emerging mechanisms involving in “beiging” of WAT. ADIPOR, adiponectin receptors; ALK, anaplastic lymphoma kinase; AR, adrenergic receptor; CGI-58, comparative gene identification-58; Clstn3β, calsyntenin 3β; CXCL14, C-X-C motif chemokine ligand-14; EODF, every-other-day fasting; ER, endoplasmic reticulum; IRE1α, inositol-requiring enzyme 1α; PPARγ, peroxisome proliferation-activated receptor gamma; PRDM16, protein PR domain containing 16; TH, tyrosine hydroxylase; Zfp423, C2H2 zinc-finger protein. The content in the boxes corresponds to the relevant mechanism and the asterisk indicates the progress of “beiging” does not involve β-adrenergic pathway. The signs (+/-) in red represent the activation/inhibition status while the arrows in red mean the elevating level of related substance. Figure created using BioRender (https://biorender.com/).