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The current global diabetes epidemic is driven by obesity. However, many obese individuals do not develop insulin resistance or the metabolic complications. Inappropriate expansion of the subcutaneous adipose cells leads to hypertrophic obesity characterized by a dysregulated adipose tissue with insulin resistance and inflammation. Here, we discuss the limited expandability of the subcutaneous adipose tissue, which, when exceeded, promotes ectopic fat accumulation and metabolic complications. Hypertrophic obesity is associated with an inability to recruit and differentiate new subcutaneous adipose cells. This is not due to lack of precursor cells but to an inability to induce their commitment and differentiation through inactivation of canonical WNT signaling and allowing bone morphogenetic protein 4 (BMP4) to initiate commitment of precursor cells. The WNT-inducible secreted protein 2 (WISP2) links WNT and BMP4 signaling. It is highly expressed in early adipogenic precursor cells and inhibits adipogenesis through dual mechanisms; cytosolic WISP2 forms a complex with ZNF423, a transcriptional activator of peroxisome proliferator–activated receptor γ (PPARγ), and this complex is dissociated by BMP4 allowing ZNF423 to enter the nucleus and initiate PPARγ activation. However, WISP2 is also a secreted protein that, through unclear mechanisms, directly inhibits PPARγ activation. WISP2 expression in human subcutaneous adipose tissue is associated with hypertrophic obesity, markers of ectopic fat accumulation, and degree of insulin resistance. Thus, WISP2 is a novel secreted adipokine at the crossroad between WNT and BMP4 signaling that can play a critical role for the development of hypertrophic obesity and associated metabolic complications. Identifying the receptor and signaling pathways for WISP2 can open up new avenues for treatment. The current global epidemic of obesity is a huge challenge to society and imposes increasing costs on the health care system because obesity is associated with several negative consequences to our health, including type 2 diabetes (T2D), cardiovascular disease, and …
Gustafson et al. (Thu,) studied this question.