Emerging Complexities in Adipocyte Origins and Identity

Abstract

The global incidence of obesity and its comorbidities continues to rise along with a demand for novel therapeutic interventions. Brown adipose tissue (BAT) is attracting attention as a therapeutic target because of its presence in adult humans and high capacity to dissipate energy as heat, and thus burn excess calories, when stimulated. Another potential avenue for therapeutic intervention is to induce, within white adipose tissue (WAT), the formation of brown-like adipocytes called brite (brown-like-in-white) or beige adipocytes. However, understanding how to harness the potential of these thermogenic cells requires a deep understanding of their developmental origins and regulation. Recent cell-labeling and lineage-tracing experiments are beginning to shed light on this emerging area of adipocyte biology. We review here adipocyte development, giving particular attention to thermogenic adipocytes.

Keywords: UCP1; adipose tissue development; beige adipocyte; brite adipocyte; brown adipocyte; lipodystrophy; obesity; thermogenesis; white adipocyte.

Figure I

The distribution of brown adipose tissues in human adults (left) and infants (right)

Figure 1. The Anatomy of adipose tissue and its plasticity in response to temperature

(A) General morphological and functional differences between brown, brite/beige and white adipocytes. (B) Anatomical distribution of major adipose tissue depots. iBAT: interscapular BAT; sBAT: subscapular BAT; cBAT: cervical BAT: asWAT: anterior subcutaneous WAT; ingWAT: inguinal WAT; mWAT: mesenteric WAT; rWAT: retroperitoneal WAT; pgWAT: perigonadal WAT. The peritoneum is represented by a dotted line (C) Brown and scWAT remodeling in 13-week old male C57Bl/6 mice is temperature sensitive. In mice living in their thermoneutral zone (~30°C for 4 weeks), brown adipocytes appear characteristically like white adipocytes, as shown here by H&E staining. At standard mouse housing temperatures (~22°C), BAT assumes its familiar “active” appearance. At significantly colder temperatures (progressively decreasing form 22 to 6°C in a period of 4 weeks), scWAT remodels, and appears characteristically more like BAT in mice living in standard housing conditions. Perigonadal visceral WAT is largely resistant to temperature-induced remodeling.

Figure 2. Current models depicting the developmental origins of adipocytes based on in vivo lineage tracing/cell labeling studies

(A) Representation of Pax3-Cre, Myf5-Cre, Prx1-Cre, and Wt1-Cre labeling of mature adipocytes in young mice. It should be noted that Cre-labeling is only a measure of promoter activity. Although it is often assumed that Cre activity mirrors expression of the gene product controlled by that promoter [See Box 3]. (B) Lineage model depicting the origin of skeletal muscle, most brown adipocytes, and many white adipocytes from a common Myf5/Pax3⁺ multipotent precursor cell. It is alternatively possible that multiple lineages independently express Myf5/Pax3. Lipid droplets in both brown and white adipocytes can appear unilocular or multilocular depending upon the temperature. (C) Lineage model depicting subcutaneous white and brite adipocyte origins. It remains unclear if and when white and brite lineages diverge, and whether the primary mechanism of brite adipocyte formation is by de novo adipogenesis from precursors or by inter-conversion from existing mature adipocytes.