Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

Abstract

Aims/hypothesis: Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known.

Methods: We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed.

Results: The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1).

Conclusions/interpretation: These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

Fig. 1

Improved glucose tolerance in female Socs3 AKO mice. (a) Adipose tissue Socs3 mRNA in WT (white bars) and Socs3 AKO mice (black bars) following 16 weeks consumption of a chow or HFD. Body mass of female (b) and male (c) WT (white symbols) and Socs3 AKO mice (black symbols) fed chow (circles) or HFD (triangles, inverted triangles). (d) Glucose tolerance (1 g/kg body mass) and (e) AUC (mmol/l×min) in female WT and Socs3 AKO mice fed a chow or HFD for 16 weeks. AU, arbitrary units. Data are mean ± SEM, n=6 for real-time quantitative PCR data and n=14–16 for body mass and GTT data. ^†p<0.0001 relative to chow control; *p<0.05, ***p<0.0001 relative to WT for same diet

Fig. 2

Adiposity, adipose tissue cell size and adipose-tissue AMPK activity is not altered in Socs3 AKO mice. (a) Body fat composition assessed by CT analysis (representative image with quantification). (b) Adipose tissue histology (haematoxylin and eosin [H&E] stain) from WT and Socs3 AKO mice fed chow and HFD (representative image with quantification of adipose-tissue cell size). Phosphorylation of AMPK T172 (c) and ACC S79 (d) in adipose tissue from WT and Socs3 AKO mice fed chow or HFD. White bars, WT mice; black bars, Socs3 AKO mice. AU, arbitrary units. Data are means ± SEM, n=6–8. ^†p<0.001 relative to chow control

Fig. 3

Improved whole-body insulin sensitivity and increased FDG uptake in adipose tissue of Socs3 AKO mice. (a) Reduced fasting glucose and (b) insulin levels in HFD-fed Socs3 AKO mice. (c) Increased insulin-stimulated FDG uptake into adipose tissue but not muscle of Socs3 AKO mice fed an HFD. White bars, WT mice; black bars, Socs3 AKO mice. Data are mean ± SEM, n=12–16 for blood glucose and insulin, n=6 for FDG uptake. ^†p<0.05 relative to chow control; *p<0.05 relative to WT for same diet

Fig. 4

Increased adipose tissue IRS1 content and phosphorylation in HFD-fed Socs3 AKO mice despite normal increases in JNK and IKK phosphorylation. (a, b) Adipose tissue IRS1 production and IRS1 Y1222 phosphorylation, (c) Akt (Thr308) and (d) Akt (Ser473) phosphorylation in adipose tissues of WT and Socs3 AKO mice fed a chow or HFD following a bolus of insulin. Phosphorylation of JNK (e) and IKK (f) in adipose tissue of WT and Socs3 AKO mice fed a chow or HFD. AU, arbitrary units. Data are mean ± SEM, n=8. ^†p<0.05 relative to chow control; *p<0.05 relative to WT for same diet