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 extended this observational work by an interventional study of overfeeding both IS and IR individuals matched for age, gender and body weight (McLaughlin et al, Diabetes, 2016; 65(5):1245-54). To test the hypothesis that obese, IS individuals possess adaptive adipose cell/tissue responses, they measured subcutaneous adipose cell size, insulin suppression of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or IR. At baseline, IR subjects exhibited significantly greater visceral adipose tissue (VAT), intrahepatic lipid (IHL), plasma free fatty acids, adipose cell diameter, and percentage of small adipose cells. With weight gain (3.1 1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin suppression of lipolysis and only 8% worsening of insulin-mediated glucose uptake (IMGU). Alternatively, IS subjects demonstrated significant adipose cell enlargement; decrease in the percentage of small adipose cells; increase in VAT, IHL, and lipolysis; 45% worsening of IMGU; and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL and VAT and decrease in insulin suppression of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between development of insulin resistance and changes in adipose cell size, VAT, IHL, and insulin suppression of lipolysis highlight these factors as potential mediators between obesity and insulin resistance.
