Loss of White Adipose Hyperplastic Potential Is Associated with Enhanced Susceptibility to Insulin Resistance

Abstract

SUMMARY Fat mass expansion occurs by adipocyte hypertrophy or recruitment of differentiating adipocyte progenitors, the relative balance of which may impact systemic metabolism. We measured adipogenesis in murine subcutaneous (sWAT) and visceral white adipose tissue (vWAT) using stable isotope methodology and then modeled adipocyte turnover. Birth and death rates were similar within depots; however, turnover was higher in vWAT relative to sWAT. In juvenile mice, obesity increased adipogenesis, but in adults, this was only seen in vWAT after prolonged high-fat feeding. Statistical modeling suggests differentiation of adipocyte progenitors without an accompanying self-renewing division step may partially explain the age-dependent decline in hyperplastic potential. Additional metabolic interrogation of obese mice demonstrated an association between adipocyte turnover and insulin sensitivity. These data therefore identify adipocyte hypertrophy as the dominant mechanism of adult fat mass expansion and support the paradoxical concept that metabolic disease ensues due to a failure of adipose tissue plasticity.

Adipocyte hypertrophy-hyperplasia balance contributes to weight loss after bariatric surgery

“…Our finding of an association between DM and decreased preadipocyte frequency are consistent with previous studies, 14,16,17 and confirm prior data published by our group in a smaller cohort that constitute a subset of the data in the present manuscript. 6 Decreased preadipocyte frequency and proliferative capacity is associated with obesity and metabolic disease in some, 6,14,[16][17][18] but not all 19 studies.…”

“…6 Decreased preadipocyte frequency and proliferative capacity is associated with obesity and metabolic disease in some, 6,14,[16][17][18] but not all 19 studies. These conflicting literature may result from patient heterogeneity, wide intrinsic variability in human preadipocyte frequency, 19,20 and different techniques used to quantify preadipocytes.…”

Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity

“…Given that impaired adipogenesis is also associated with insulin resistance (6,31,32), we speculate that a decline in IGF-1-mediated adipogenesis is one factor linking advanced age to insulin resistance. How might such a mechanism be reconciled with the reduction in insulin resistance reported in the contexts of growth hormone deficiency or resistance, in which levels of downstream IGF-1 are also reduced (33)(34)(35)?…”

“…One such example is adipose tissue, for which estimated rates of homeostatic adipocyte turnover differ by over one order of magnitude (1)(2)(3)(4)(5)(6)(7). Landmark studies leveraging the global carbon-14 pulse that ensued in the 20th century after above-ground nuclear testing applied carbon-14 birth dating and population modeling to retrospectively infer the dynamics of human neurogenesis (8), cardiogenesis (9), adipogenesis (1), and adipocyte lipid turnover (10).…”

Heterogeneity of adipose tissue in development and metabolic function

“…2), which some studies have shown occurs primarily in the visceral fat depots of mice (Kim et al, 2014;Wang et al, 2013). Other studies have shown an association between hyperplasia and subcutaneous fat depots (Tchkonia et al, 2013), with a higher capacity for adipogenesis observed in femoral rather than in abdominal subcutaneous depots in humans (Tchoukalova et al, 2010).…”