Towards a Better Understanding of Beige Adipocyte Plasticity

Abstract

Beige adipocytes are defined as Ucp1⁺, multilocular adipocytes within white adipose tissue (WAT) that are capable of thermogenesis, the process of heat generation. In both mouse models and humans, the increase of beige adipocyte population, also called WAT browning, is associated with certain metabolic benefits, such as reduced obesity and increased insulin sensitivity. In this review, we summarize the current knowledge regarding WAT browning, with a special focus on the beige adipocyte plasticity, collectively referring to a bidirectional transition between thermogenic active and latent states in response to environmental changes. We further exploit the utility of a unique beige adipocyte ablation system to interrogate anti-obesity effect of beige adipocytes in vivo.

Keywords: WAT browning; beige adipocyte; metabolism; thermogenesis.

Figure 1

Players that are involved in beige adipocyte formation. There are two major routes to generate the Ucp1⁺ and multilocular beige adipocytes in white adipose tissue (WAT) by various physiological stimuli, such as cold, nutrient excess, burn injury, exercise, and cancer cachexia. The first route is through de novo beige adipogenesis from PDGFRα⁺, or PDGFRb⁺ or MyoD⁺ progenitors residing in WAT. The other route is through transdifferentiation from existing white adipocytes. Although the sympathetic nervous system (SNS) is the major driver for beige adipocyte formation, various types of immune cells and circulating hormones (thyroid hormone, Natriuretic peptides, FGF21, Irisin, IL-6) and metabolites (succinate, lactate, and bile acid) can influence beige adipocyte formation via either route.

Figure 2

Beige adipocyte specific ablation in vivo. (a) Diagram showing beige adipocyte ablation strategy. In Ucp1-Cre:Rosa-STOP-iDTR mice at room temperature, DT injection at ~3 weeks of age induces cell death of Ucp1⁺ brown adipocytes in interscapular BAT (iBAT) and beige adipocytes in iWAT within 3 days. Brown adipocytes gradually repopulate the BAT in 3–5 weeks, while Ucp1⁺ beige adipocytes remain absent in iWAT. (b) Representative H&E staining of iBAT and iWAT from Ucp1-Cre:Rosa-STOP-iDTR^het mice prior to 3 days or 5 weeks post-DT injection. Scale bar: 200 μm. Black arrows: Multilocular brown and beige adipocytes.

Figure 3

Beige adipocyte plasticity. During postnatal development, thermogenic active beige adipocytes (positive for Ucp1 and multilocular in morphology) in iWAT peak at ~3 weeks of age, due to de novo beige adipogenesis from progenitors (“genesis”). These Ucp1⁺-lineage beige adipocytes are unstable by default, becoming latent beige adipocytes (negative for Ucp1 and unilocular in morphology) at adult stage (~8 weeks of age) at room temperature (RT). Under 4 °C cold stimulation, their beige characteristics are restored (“renaissance”). The “maintenance” of beige adipocytes refers to the process that thermogenic active beige adipocytes remain their thermogenic activity, which requires persistent cold stimulation. Withdrawal from cold or nutrient excess can convert the active beige adipocytes back to the latent stage.

Figure 4

Central role of HDAC4 in white adipocytes during beige adipocyte plasticity. (a) Left: Phenotypes of beige adipocyte genesis and renaissance in mouse models. Right: Blackline, dark-blue down arrow and red up arrow indicate HDAC4 activity in Ucp1⁺ and Ucp1⁻ lineage adipocytes. (b) Proposed model: Beige adipocyte plasticity, including renaissance and maintenance, is mainly regulated by cAMP- and HDAC4-dependent signaling in Ucp1⁻-lineage white adipocytes in a non-cell autonomous fashion. Shaded box: Diagram showing salt-inducible kinases (SIKs)–HDAC4 pathway in white adipocytes. Upon cold-stimulation, catecholamine released by sympathetic nerves binds to the beta-adrenergic receptors (βARs) to induce cAMP production by activating adenylate cyclase-stimulating G alpha subunit (GNAS). cAMP inhibits SIKs, leading to dephosphorylation and nucleus-translocation of class IIa HDACs (such as HDAC4). Liver kinase b 1 (LKB1) phosphorylates and activates SIKs, causing phosphorylation and nuclear exclusion of class II HDACs. Abbreviations: Ucp1: Uncoupling protein 1; iWAT: Inguinal white adipose tissue; cAMP: Cyclic adenosine monophosphate; HDAC4: Class IIa histone deacetylase 4.