Molecular and cellular regulation of thermogenic fat

Abstract

Thermogenic fat, consisting of brown and beige adipocytes, dissipates energy in the form of heat, in contrast to the characteristics of white adipocytes that store energy. Increasing energy expenditure by activating brown adipocytes or inducing beige adipocytes is a potential therapeutic strategy for treating obesity and type 2 diabetes. Thus, a better understanding of the underlying mechanisms of thermogenesis provides novel therapeutic interventions for metabolic diseases. In this review, we summarize the recent advances in the molecular regulation of thermogenesis, focusing on transcription factors, epigenetic regulators, metabolites, and non-coding RNAs. We further discuss the intercellular and inter-organ crosstalk that regulate thermogenesis, considering the heterogeneity and complex tissue microenvironment of thermogenic fat.

Keywords: energy expenditure; epigenetic modification; inter-organ crosstalk; intercellular regulation; thermogenic fat; transcription factor.

Figure 1

Molecular regulation of thermogenesis of brown and beige adipocytes. (A). Beige pre-adipocyte and brown pre-adipocyte differentiate into beige adipocyte and brown adipocyte respectively. In specific conditions, white adipocytes convert into beige adipocytes, a process called “browning”. Under cold exposure or other signal induction, differentiated brown and beige adipocytes undergo thermogenesis, accompanied by higher glucose and fatty acid uptake, UCP1 expression, and uncoupled respiration. (B). Regulatory mechanisms behind thermogenesis of brown and beige adipocytes including the following 4 parts: 1. Transcriptional regulation; 2. Epigenetic modulation; 3. Non-coding RNA regulation; 4. Metabolic reprogramming. UCP1 is one of the most critical thermogenic genes, and its expression is critical for uncoupled cellular respiration. There are three core regulators in the thermogenesis program regulation: PPARγ, PRDM16, and PGC1α, and most other regulators regulate thermogenesis through them. Double-headed arrows indicate protein interaction and complex formation, while arrow-headed and bar-headed lines show inducing and inhibiting effects.

Figure 2

Cellular interaction between thermogenic adipocytes and resident cells. (A). Interaction between sympathetic nerve and thermogenic adipocyte. Sympathetic nerve secretes norepinephrine (NE) that promotes white adipocyte browning and brown adipocyte activation; in turn, beige adipocytes and brown adipocytes promote nerve remodeling through secreting neurotrophic factor, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neuregulin-4 (NRG4) as well as Zinc. (B). Interaction between vascular endothelial cells and thermogenic adipocyte. Vascular endothelial cells secrete endothelin 1 (EDN1) and nitric oxide (NO) to promote the thermogenic function of brown and beige adipocytes. Besides, the secreted EDN1 and platelet-derived growth factor C (PDGF-C) also regulate the adipogenesis of preadipocytes. Reciprocally, thermogenic adipocytes and their progenitors secrete several factors that promote angiogenesis in adipose tissue. ANGPT2, angiopoietin 2; VEGF, vascular endothelial growth factor. (C). Interaction between resident immune cells and thermogenic adipocytes. Various cytokines and signals mediate the bi-directional communication between thermogenic fat and different kinds of immune cells.

Figure 3

Inter-organ communications between thermogenic fat depots and different organs. Multiple organs, such as the brain, liver, muscle, and gut, can have crosstalk with thermogenic fat depots. The communications between these organs and the thermogenic fat depot mainly involve the secretion of different kinds of molecules, including peptide hormones, lipokines, glucocorticoids, and bile acids. Dashed arrows mean the secretion of factors; solid arrows mean positive effects; blunt-end lines mean inhibitory effects.