Brown and Beige Fat: Physiological Roles beyond Heat Generation

Abstract

Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.

Figure 1. Brown adipocyte development

A multipotent cell population in the somitic mesoderm gives rise to: dorsal dermis, skeletal muscle, brown adipocytes and white adipocytes in certain depots. EBF2 marks committed brown preadipocytes and may also regulate the commitment process from upstream stem cells. EWS controls the expression of BMP7 by brown fat precursor cells, which in turn promotes brown adipocyte differentiation by acting in an autocrine manner. EBF2, PRDM16, C/EBP-β, and ZFP516 specifically regulate the induction of brown fat-specific genes during the differentiation process. PRDM16 binds and activates C/EBP-β, PPARγ, PPARα, Thyroid receptor (not shown) and ZFP516. Cold exposure/norepinephrine (NE) activates brown adipocytes to express high levels of thermogenic genes; this activation process is controlled, in large part, by PGC1α which interacts with IRF4 (Kong et al., 2014) and various Nuclear Receptors (NRs). MYF5 or MYOD control myoblast cell commitment, while MYOD, MYOG and MRF4 regulate myocyte differentiation and maturation. TLE3 plays an important role in driving a white fat-specific differentiation program.

Figure 2. Beige fat biogenesis

(Top panel) In inguinal WAT, β-adrenergic stimulation stimulates the de novo differentiation of EBF2+ precursor cells into beige adipocytes. In the absence of stimuli, these beige adipocytes lose their expression of UCP1 and their multilocular morphology and could be considered as “masked”. The thermogenic characteristics of these cells can be re-activated by repeated stimulation. (Bottom panel) In epididymal WAT, bipotent precursor cells can be induced to undergo beige adipocyte differentiation in response to cold/β-agonist. Under other conditions (such as high fat diet), these cells may differentiate into white adipocytes.

Figure 3. Physiological roles of brown and beige fat in energy metabolism

Thermogenic and non-thermogenic functions of brown and beige adipocytes are listed.