ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis
Aaron L. Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F. Vatner, Gerald I. Shulman, Sonia Caprio
Aaron L. Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F. Vatner, Gerald I. Shulman, Sonia Caprio
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Clinical Research and Public Health Endocrinology Metabolism

ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis

Abstract

BACKGROUND This study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR.METHODS Thirteen adolescents who were insulin sensitive (IS) and 17 adolescents with IR and obesity underwent a 3-hour oral glucose tolerance test and MRI to measure abdominal fat distribution and liver fat content. Lipolysis was determined by glycerol turnover ([2H5]-glycerol infusion) and adipose triglyceride lipase (ATGL) phosphorylation (Western blot) from SAT samples biopsied prior to and 30-minutes following insulin infusion during a hyperinsulinemic-euglycemic clamp (HEC).RESULTS Glycerol turnover suppression during the HEC (first step) was lower in participants with IR compared with those with IS. Prior to insulin infusion, activated ATGL (reflected by the p-ATGL (Ser406)-to-ATGL ratio) was greater in participants with IR compared with those with IS and suppressed in response to a 30-minute insulin exposure in participants with IS, but not in those with IR. Lastly, greater ATGL inactivation is associated with greater glycerol suppression and lower liver fat.CONCLUSIONS Insulin-mediated inhibition of adipose tissue lipolysis via ATGL is dysregulated among adolescents with IR compared with those with IS, thereby serving as a vital mechanism linking glucose and insulin dysregulation and ectopic lipid storage within the liver.FUNDING This work was supported by funding from the NIH (R01-HD028016-25A1, T32- DK-007058, R01-DK124272, RO1-DK119968, R01MD015974, RO1-DK113984, P3-DK045735, RO1-DK133143, and RC2-DK120534) and the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.

Authors

Aaron L. Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F. Vatner, Gerald I. Shulman, Sonia Caprio

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Figure 1

In response to the HEC, no differences in plasma glucose were observed between groups.

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In response to the HEC, no differences in plasma glucose were observed b...
(A) Plasma insulin concentrations were greater in participants with IR compared with those with IS throughout the HEC, whereas relative increases in plasma insulin concentrations (compared with time point 0) were similar in both groups (B and C). Peripheral insulin sensitivity (M; adjusted for plasma insulin concentrations) during the second step of the HEC was lower in participants with IR compared with those with IS (D). Insulin-induced suppression of plasma non esterified fatty acid (NEFA) concentrations tended to be lower in participants with IR compared with those with IS during the first step of the HEC and were suppressed similarly in both groups throughout the HEC (E and F). Glycerol turnover rates reached steady state during each step of the HEC in both participant groups, and glycerol turnover rates were lower in participants with IR compared with those with IS throughout step 1 of the HEC (G). Consistent with these findings, insulin-induced suppression of glycerol turnover during the first step of the HEC was lower in participants with IR compared with those with IS (H). Finally, AT-IR was elevated in participants with IR compared with those with IS at the initiation of HEC and remained elevated during the first step. Similarly, the level of suppression tended to be lower in participants with IR compared with those with IS before near complete suppression was observed in both participant groups (I and J). Differences in continuous data were determined by Student’s t test or Mann–Whitney U analysis, and the impact of time on plasma protein and indices of insulin resistance in response to HEC tests were examined by repeated measures ANOVA. P values less than 0.05 were considered significant. Data are presented as means ± SD or IQR (25%, 75%). *P > 0.05.