ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis
Aaron L. Slusher, … , Gerald I. Shulman, Sonia Caprio
Aaron L. Slusher, … , Gerald I. Shulman, Sonia Caprio
Published March 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e184740. https://doi.org/10.1172/JCI184740.
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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 2

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.

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Glycerol turnover rates reached steady state during each step of the HEC...
(A) 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 (B). Representative Western blot images for the ratios of p-ATGL (Ser406)-to-ATGL and p-HSL (Ser660)-to-HSL prior to and in response to acute, low-dose insulin infusion (30 minutes following the initiation of 8 mU·m–2·min–1 insulin). Prior to insulin, the ratio of p-ATGL (Ser406)-to-ATGL was greater in IR compared with IS participants, whereas a decrease in the ratios of p-ATGL (Ser406)-to-ATGL was observed in participants with IS, but not IR, following insulin infusion (C). Lastly, no differences in the ratio of p-HSL (Ser660)-to-HSL protein were observed between IS and IR participant groups prior to insulin. However, p-HSL (Ser660)-to-HSL decreased in participants with IS, but not those with IR, following insulin infusion (D). Lastly, the reduced activation of the ratio of p-ATGL (Ser406)-to-ATGL, indicated by the percent change (before the start to 30 minutes after the start of insulin infusion), was associated with greater suppression glycerol (step 1; E) and lower PDFF (F). Differences in continuous data were determined by Student 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 2-way repeated measures ANOVA. Additionally, differences in the phosphorylation ratios were compared by using a 2-way repeated measures ANOVA and Pearson’s correlations were used to examine the relationship of ATGL protein analysis with indices of insulin resistance. P values less than 0.05 were considered significant. Data are presented as means ± SD or IQR (25%, 75%). *P > 0.05.