Adipose Tissue Remodeling in Pathophysiology

Abstract

Rather than serving as a mere onlooker, adipose tissue is a complex endocrine organ and active participant in disease initiation and progression. Disruptions of biological processes operating within adipose can disturb healthy systemic physiology, the sequelae of which include metabolic disorders such as obesity and type 2 diabetes. A burgeoning interest in the field of adipose research has allowed for the elucidation of regulatory networks underlying both adipose tissue function and dysfunction. Despite this progress, few diseases are treated by targeting maladaptation in the adipose, an oft-overlooked organ. In this review, we elaborate on the distinct subtypes of adipocytes, their developmental origins and secretory roles, and the dynamic interplay at work within the tissue itself. Central to this discussion is the relationship between adipose and disease states, including obesity, cachexia, and infectious diseases, as we aim to leverage our wealth of knowledge for the development of novel and targeted therapeutics.

Keywords: adipose tissue; browning; burns; cachexia; fibrosis; infectious diseases.

Figure 1

Adipose dynamics in healthy and pathological states. (a) Adipose tissue grows through both hypertrophy (increase in cell size) and hyperplasia (increase in cell number). While both processes allow healthy and functional expansion of fat, an excessive increase in size via caloric overnutrition induces a pathological state characterized by inflammation, hypoxia, and decreased blood supply. (b) Unresolved chronic inflammation as a result of obesity or other metabolic disorders remodels adipose tissue into a fibrotic state characterized by the accumulation of ECM proteins and persistent hypoxia that is difficult to reverse, limiting the dynamism of adipose depots. Senescent cells, characterized by irreversible cell cycle arrest, are a product of metabolic disorders and aging. The SASP maintains a proinflammatory environment and impedes the differentiation of adipocyte precursors into metabolically beneficial beige adipocytes. This maladaptive state has detrimental sequelae such as insulin resistance, poor glucose uptake, and ectopic fat deposition (lipotoxicity). Abbreviations: ECM, extracellular matrix; HIF1α, hypoxia-inducible factor 1α; IL, interleukin; MCP1, monocyte chemoattractant protein 1; PDGF, platelet-derived growth factor; SASP, senescence-associated secretory phenotype; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha.

Figure 2

Mechanisms of adipocyte thermogenesis. (a) Classically, β3-adrenergic stimulation increases cytosolic cAMP, activating PKA and promoting the thermogenic program, thus dissipating the mitochondrial proton gradient as heat through UCP1 and sacrificing ATP production. (b) Absence of UCP1, however, via its genetic ablation or in mammals lacking a functional thermogenin, does not impede thermogenesis. Alternative futile cycles involving calcium, creatine, and fatty acids also generate heat via the cleavage of ATP without accomplishing functional work. Abbreviations: cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; SERCA, sarco/endoplasmic reticulum Ca²⁺ ATPase; TNAP, tissue-nonspecific alkaline phosphatase; UCP1, uncoupling protein 1.

Figure 3

Pathological adipose tissue remodeling in cachexia and burns. (a) While browning is often heralded for its benefits in metabolic disorders, increased lipolysis and UCP1-mediated thermogenesis appears to be detrimental in cachectic conditions such as in cancer and severe burns. (b) Severe burns, in particular, are demarcated by a prolonged hypermetabolic response. Browning of subcutaneous white adipose tissue in addition to increased lipolysis and a proinflammatory environment contribute to systemic lipotoxicity, organ failure, sepsis, and death. Abbreviations: IL, interleukin; OXPHOS, oxidative phosphorylation; PTHrP, parathyroid-hormone-related protein; UCP1,uncoupling protein 1.