Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis

Abstract

Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. Two types of thermogenic adipocytes with distinct developmental and anatomical features exist in rodents and humans: classical brown adipocytes and beige (also referred to as brite) adipocytes. While classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside with white adipocytes and emerge in response to certain environmental cues, such as chronic cold exposure, a process often referred to as "browning" of white adipose tissue. Recent studies indicate the existence of beige adipocytes in adult humans, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, including type 2 diabetes. This Review aims to cover recent progress in our understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT.

Figure 3. External and internal factors that regulate beige adipocyte development under lean and obese conditions.

Beige adipocyte development is induced by the indicated stimuli and mediated by the listed endocrine factors. This process is associated with increased energy expenditure, reduced body weight, and improved insulin sensitivity. Under obese conditions, beige adipocyte development is impaired through multiple factors, including but not limited to reduced sympathetic nervous system (SNS) activity and increased activation of signaling pathways that inhibit beige adipocyte development. Impaired beige adipocyte development is associated with reduced energy expenditure, increased body weight, reduced insulin sensitivity, and development of hepatic steatosis.

Figure 2. Developmental origins of brown and beige adipocytes.

(A) Classical brown adipocytes originate from a subset of dermomyotomes that express En1, Pax7, and Myf5. Classical brown adipocytes express several markers, including Ucp1, Pgc1a, and Cidea, and classical brown-selective markers, such as Zic1. (B) Beige adipocytes in WAT originate from MYF5-negative PDGFRα-positive precursors of mesodermes. A subset of beige adipocytes arises from MYH11-positive smooth muscle–like precursors. Beige adipocyte differentiation is induced by environmental cues, such as chronic cold exposure, exercise, and PPARγ agonists. Beige adipocytes express several markers, including Ucp1, Pgc1a, and Cidea, and beige-selective markers, such as Cd137, Tbx1, Tmed26, and Cited1. These cells may be derived from (i) defined beige precursors, (ii) directed differentiation from white precursors, or (iii) transdifferentiation from white adipocytes in a differentiated state. The dashed lines represent hypothetical models that require further investigation.

Figure 1. Anatomical locations of thermogenic adipocytes in mice and humans.

(A) In rodents, interscapular BAT and perirenal BAT are composed of classical brown adipocytes. Beige adipocytes are largely found in subcutaneous WAT (anterior and inguinal WAT) and are highly recruitable (a process referred to as “browning” of WAT) by certain external cues. (B) Adult human BAT is located mainly in the cervical, supraclavicular, and paravertebral regions. In infants, BAT is found in the interscapular and perirenal regions.