Adipogenesis and Insulin Resistance

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

One of the main findings of our research is that adipose cells have a unique size distribution. It is not a typical unimodal Gaussian distribution but has a Gaussian-like peak of large cells and an exponential-like tail of small cells. We have interpreted the Gaussian peak as representing mature adipocytes and the tail as newer cells in the process of growing as they take up lipid. In some individuals, both human and rodent, an additional peak of cells with intermediate diameter can be observed, which may even move to the right with time, suggesting a bolus of cells recruited close together in time that grows and joins the peak of mature cells. We have correlated the characteristics of the size distributions, chiefly the fraction of small cells and the typical size of the large cells, with insulin resistance or sensitivity in a variety of study populations. Our initial study, in collaboration with the McLaughlin lab at Stanford University, examined moderately obese subjects (BMI near 30 kg/m2) who were insulin sensitive (IS) or insulin resistant (IR) and found that the insulin resistant group had an increased proportion of small cells. This was interpreted as a signature of impaired adipocyte development, which could result in impaired lipid storage capacity and lead to spillover of lipid to other organs poorly equipped to handle the fat load. Such spillover, or ectopic fat has been proposed to cause insulin resistance in muscle and liver and impaired insulin secretion in the pancreas. The study noted a trend toward larger large cells among the IR subjects, but this did not reach statistical significance. One would expect larger large cells given a smaller proportion of large cells if BMI and total fat mass are the same between the groups, as they were by design. A follow-up study with a larger group of subjects and a broader range of BMI has confirmed the increased proportion of small cells as well as larger large cells (see Ref. # 1 of the 2014 report). The increased size was also reported by us in Ref. # 1 of the 2012 report. A considerable body of evidence from other studies supports the notion that large cells are intrinsically less efficient at storing lipid than small cells. Our collaborators have studied whether the cardiovascular benefits of weight loss in overweight individuals is related to changes in fat-cell size distributions. They confirmed that improvements in insulin sensitivity among insulin-resistant individuals and in several cardiovascular risk factors are correlated with reductions in fat-cell size independent of changes in body weight and body fat (McLaughlin et al, Nutr Metab Cardiovasc Dis. 2019; 29(1):62-68; PMID: 30497926).