Mechanisms and metabolic implications of regional differences among fat depots

Abstract

Fat distribution is closely linked to metabolic disease risk. Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging. Preadipocyte replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance. How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood. Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question.

Figure 1. Anatomy of Major Fat Depots in Rodents and Humans

Several different names for particular fat depots in rodents (A) and humans (B) are used, as are different groupings of fat depots for physiological and clinical studies. The names and anatomies of the fat depots reviewed here are indicated.

Figure 2. Regional Variation in Fat-Tissue Cell Dynamics

(A) Regional variation in fat-tissue cell dynamics. Preadipocytes arise from resident multipotent mesenchymal progenitor cells, which are generally associated with blood vessels and may be related to endothelial cells or pericytes, and can possibly become committed to brown fat, myocyte, osteocyte, chondrocyte, or macrophage lineages (see Supplemental Information for a note regarding nomenclature). Circulating progenitors may contribute, especially to visceral fat development (Crossno et al., 2006). (B) Committed preadipocytes can replicate, differentiate into adipocytes, or possibly revert into multipotent progenitors again. At least two interconvertible preadipocyte subtypes exist; one is more capable of replication, differentiation, and resistance of apoptosis than the other. Preadipocytes can be induced to differentiate by IGF-1 and other stimuli. Differentiated fat cells vary lipid content through esterifying exogenous fatty acids to glycerol, de novo lipogenesis, or fatty-acid release through lipolysis. (C) Key transcription factors involved in adipogenesis. IGF-1 and other signals combine to induce adipogenesis, with early increases in cyclic AMP (cAMP)-and protein kinase A-mediated phosphorylation and activation of CREB, which along with GSK3β contributes to activation of C/EBPβ. Activated C/EBPβ forms homodimers or heterodimers with glucocorticoid-induced C/EBPδ that enhance PPARγ expression and activity. Upon binding to a lipid ligand, as well as to RXRα and its retinoid ligands, PPARγ transactivates C/EBPα, the other major adipogenic transcription factor. PPARγ and C/EBPα cooperate to maintain their own expression, activate SREBP1c (ADD1 in mice), and, together with SREBP1c, transactivate around 2,500 downstream differentiation-dependent genes. This leads to the acquisition of capacities for adipogenesis, lipid storage, insulin responsiveness, and lipolysis; increased secretion of some adipokines (e.g., leptin) and decreased secretion of others (e.g., PAI-1); and changes in extracellular matrix component production, micro-RNAs, histones, and chromatin structure (reviewed in Cristancho and Lazar, 2011; Tang and Lane, 2012).

Figure 3. Mechanisms of Fat-Tissue Growth during the Progression of Obesity Vary among Depots

Some regions of human subcutaneous fat, which is specialized to provide long-term nutrient storage, grow through increases in fat cell number, such as femoral fat (A), and others grow through increases in fat cell size, such as abdominal subcutaneous fat (B). Intraperitoneal fat—the omental depot, for example (C)—generally enlarges through increases in fat cell size rather than number, consistent with its role in storing and releasing nutrients rapidly and its limited space for growth. These interdepot differences are related to higher potentials of subcutaneous than visceral preadipocytes for replication and adipogenesis.