The effect of weight gain in metabolically normal or abnormal obese subjects

Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Weight gain is associated with the development and worsening of nonalcoholic fatty liver disease (NAFLD), but the mechanisms responsible for this association are not know. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. In an effort to investigate the underlying differences between MNO and MAO, we investigated the characteristics of T cells in adipose tissue from MAO subjects, MNO subjects, and lean subjects. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m2 who were matched for BMI and fat mass. Imaging and stable isotope tracers techniques were combined to evaluate the effect of moderate weight gain in 27 obese people on intrahepatic triglyceride (IHTG) content and hepatic lipid metabolism in order to elucidate the mechanisms responsible for weight-gain induced IHTG accumulation. Plasma cytokine concentrations and subcutaneous adipose tissue CD4+ T-cell populations were assessed in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of cytokine receptors Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorate, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. Also, our results demonstrate that weight gain causes an imbalance between hepatic availability and disposal of fatty acid by increasing de novo lipogenesis, reducing fatty acid oxidation, and by inadequately increasing VLDL secretion. Adipose tissue from MAO subjects had 3- to 10-fold increasese in numbers of CD4+ T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phyenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. Il-17 and Il-22 inhibited uptake of glucose in skeletal muscle isolate from rats and reduced insulin sensitivity in cultured human hepatocytes. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain—induced metabolic dysfunction. Weight gain causes and imbalance between hepatic availability and disposal of fatty acid which are likely responsible for increased IHTG accumulation. Adipose tissue from MAO people contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether such alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.