A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis

Abstract

Brown adipose tissue (BAT) is specialized to dissipate chemical energy in the form of heat as a defense against cold and excessive feeding. Interest in the field of BAT biology has exploded in the past few years because of the therapeutic potential of BAT to counteract obesity and obesity-related diseases, including insulin resistance. Much progress has been made, particularly in the areas of BAT physiology in adult humans, developmental lineages of brown adipose cell fate, and hormonal control of BAT thermogenesis. As we enter into a new era of brown fat biology, the next challenge will be to develop strategies for activating BAT thermogenesis in adult humans to increase whole-body energy expenditure. This article reviews the recent major advances in this field and discusses emerging questions.

Figure 1

Uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipocytes. (a) Hypothetical model of UCP1-dependent proton uncoupling in brown fat mitochondria. A long-chain fatty acid (LCFA) molecule directly binds to the UCP1 protein, serving as a UCP1 substrate to transport one H⁺ per transport cycle. The transported free-fatty-acid (FFA) anion needs a long, hydrophobic tail. (b) ATP inhibits the activity of UCP1 in the resting state. In response to cold stimuli or excess food intake, norepinephrine acts on the β3-adrenoceptor (β3-AR), leading to the activation of cAMP-dependent protein kinase (PKA) and the phosphorylation of hormone-sensitive lipase (HSL). FFAs are generated by cAMP-induced lipolysis or taken up from the circulation and utilized as UCP1 substrates for H⁺ transport and as substrates of β-oxidation in brown fat mitochondria (indicated by red arrows).

Figure 2

Hierarchical developmental relationships in brown and white adipocytes. The two types of thermogenic adipocytes (classical brown adipocytes and beige/brite cells) have separate developmental origins. (a) BAT and skeletal muscle originate from precursors in the dermomyotome that express Engrailed-1 (En1) and Myf5. Brown adipose fate in the somite is determined by transcriptional regulators, including PRDM16 (PRD1-BF-1-RIZ1 homologous domain–containing protein 16) and C/EBPβ(CCAAT/enhancer-binding protein-β), during embryonic development. (b) Beige/brite cells are not descended from Myf5-expressing cells. Adipocyte precursors that express PDGFα(36) differentiate into beige/brite cells mainly in subcutaneous white adipose tissue in response to several environmental cues, including chronic cold exposure, exercise, and peroxisome proliferator–activated receptor γ(PPARγ) agonists (red arrow), through the action of PRDM16. These cells appear to be derived from (i ) defined beige precursors, (ii ) directed differentiation from bipotent preadipocytes, or (iii ) transdifferentiation from mature white adipocytes. The dashed purple arrows depict hypothetical relationships that need further investigation.

Figure 3

BAT-mediated interorgan networks. Several endocrine factors regulate BAT development and thermogenesis and mediate interorgan communication with central and peripheral tissues. Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNS, central nervous system; FGF, fibroblast growth factor; TGF, transforming growth factor.