BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. 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.
METHODS. 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.
RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, 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.
CONCLUSIONS. 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.
FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.
Elisa Fabbrini, Jun Yoshino, Mihoko Yoshino, Faidon Magkos, Courtney Tiemann Luecking, Dmitri Samovski, Gemma Fraterrigo, Adewole L. Okunade, Bruce W. Patterson, Samuel Klein
(A) Hepatic, skeletal muscle, and adipose tissue insulin sensitivity in MNO (n = 12) and MAO (n = 8) subjects before (white bars) and after (black bars) weight gain. Endogenous glucose Ra in plasma and percentage of suppression of glucose Ra during low-dose insulin infusion (stage 1) of the clamp procedure (an index of hepatic insulin sensitivity). (B) Skeletal muscle glucose Rd from plasma and percentage of stimulation of glucose Rd during high-dose insulin infusion (stage 2) of the clamp procedure (an index of skeletal muscle insulin sensitivity). (C) Palmitate Ra in plasma and percentage of suppression of palmitate Ra during low-dose insulin infusion (stage 1) of the clamp procedure (an index of adipose tissue insulin sensitivity). Repeated-measures ANCOVA was used for statistical analysis, with the intervention as the within-subjects factor (before vs. after weight gain), the group as the between-subjects factor (MNO vs. MAO), and sex and race as covariates. §P < 0.01, value different from the corresponding MNO value; *P < 0.05, value different from the before–weight-gain value. Data represent the mean ± SEM (A and C) or the mean and 95% CIs (B).