Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation

Abstract

This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome.

Fig. 1

Lipid metabolism in adipocytes. Adipocytes are equipped with the biochemical machinery to function effectively as the body’s fuel store. To do this, it must mediate lipogenesis [conversion of FFA to triglycerides (TG) for storage] and lipolysis (breakdown of triglycerides to FFA and glycerol). It is also sensitive to changing nutritional cues. For example, it is insulin-sensitive [insulin stimulates glucose uptake and lipogenesis and inhibits lipolysis] and subject to adrenergic regulation [stimulates lipolysis and adaptive thermogenesis (brown adipose tissue)]. AC, adenylate cyclase; ACS, acyl-CoA synthase; AKT, AKR mouse thymoma viral proto-oncogene; AR, adrenergic receptor; HSL, hormone sensitive lipase; IR, insulin receptor; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A.

Fig. 2

The transcriptional control of adipogenesis involves the sequential activation of a transcription factor cascade. This begins with the transient expression of C/EBPβ and C/EBPδ, followed by C/EBPα, which in turn activates peroxisome proliferator-activated receptor γ 2 (PPARγ2). The latter pair is primarily responsible for switching on the broad program of adipogenesis. In addition, PPARγ exerts positive feedback on C/EBPα and acts synergistically to maintain the differentiated state. Sterol-regulatory element binding protein 1c (SREBP1c) is regulated by insulin and lipids and can activate PPARγ by inducing its expression as well as by promoting the production of an endogenous PPAR ligand. SREBP1c also activates the expression of many genes of the lipogenic program. Together, these factors contribute to the expression of genes that characterize the terminally differentiated phenotype. GATA, GATA binding protein; IBMX, 3-Isobutyl-1-methylxanthine; PEPCK, phosphoenolpyruvate carboxykinase; TZD, thiazolidinedione.

Fig. 3

Impact of adipokines on thermodynamic balance during physiological states and states of overnutrition. Potential actions in normal physiology are indicated for each adipokine. However, in pathophysiological states associated with overnutrition, these may be separated into two functional groups: adipokines whose levels or effective activity (*) are decreased (upper panel) and adipokines whose levels and/or activity are increased (lower panel). Solid lines indicate evidence for direct action. Dashed lines are indicative of putative or potential for indirect mechanisms involving other adipokines or extracellular mediators. CNS, central nervous system; TNF, tumor necrosis factor; WAT, white adipose tissue. PBEF, pre-B-cell colony enhancing factor; RBP-4, retinol binding protein-4.