Critical role of the mesenteric depot versus other intra-abdominal adipose depots in the development of insulin resistance in young rats

Abstract

Objective: Age-associated insulin resistance may be caused by increased visceral adiposity and older animals appear to be more susceptible to obesity-related resistance than young animals. However, it is unclear to what extent the portally drained mesenteric fat depot influences this susceptibility.

Research design and methods: Young high-fat-fed and old obese rats were subjected to 0, 2, 4, or 6 weeks of caloric restriction. Insulin sensitivity (S(I)) was assessed by hyperinsulinemic clamp and lean body mass (LBM) and total body fat were assessed by (18)O-water administration.

Results: Six weeks of caloric restriction caused a similar reduction in body weight in young and old animals (P = 0.748) that was not due to reduced subcutaneous fat or LBM, but rather preferential loss of abdominal fat (P < 0.05). Most notably, mesenteric fat was reduced equivalently in young and old rats after 6 weeks of caloric restriction ( approximately decrease 53%; P = 0.537). Despite similar visceral fat loss, S(I) improved less in old ( increase 32.76 +/- 9.80%) than in young ( increase 82.91 +/- 12.66%) rats versus week 0. In addition, there was significantly more reversal of fat accumulation in the liver in young (% reduction: 89 +/- 2) versus old (64 +/- 5) rats (P < 0.0001). Furthermore, in young rats, S(I) changed much more rapidly for a given change in mesenteric fat versus other abdominal depots (slope = 0.53 vs. < or =0.27 kg/min/mg per % fat). CONCLUSIONS Improved S(I) during caloric restriction correlated with a preferential abdominal fat loss. This improvement was refractory in older animals, likely because of slower liberation of hepatic lipid. Furthermore, mesenteric fat was a better predictor of S(I) than other abdominal depots in young but not old rats. These results suggest a singular role for mesenteric fat to determine insulin resistance. This role may be related to delivery of lipid to liver, and associated accumulation of liver fat.

FIG. 1.

Effect of caloric restriction on body composition. Total abdominal fat (A), epididymal fat (B), perirenal fat (C), and mesenteric fat (D) pad weights during 6 weeks of caloric restriction in young and old rats in grams represented as a percentage of week 0. Data are means ± SEMs. Significant differences were determined using two-way ANOVAs for effect of time and age, with post hoc Tukey tests for individual comparisons. *P < 0.05 for young vs. week 0 and old vs. week 0; §P < 0.05 young vs. old. CR, caloric restriction.

FIG. 2.

Glucose infusion rates necessary to maintain euglycemia. Glucose infusion rates in mg/min/kg of body wt for young and old rats exposed to 0 (A), 2 (B), 4 (C), or 6 weeks (D) of caloric restriction. Infusion rates for control rats fed ad libitum are recapitulated in each panel for comparison. Data are represented as means ± SEMs. Statistical significance was determined using ANOVAs for the effect of group with post hoc paired Student t tests. *P < 0.05 vs. control.

FIG. 3.

Effect of caloric restriction on insulin sensitivity. Whole body (A), peripheral (B), and hepatic insulin sensitivity (C) in dl/min/kg body wt (lean body mass for peripheral) per picomolar of insulin × 10⁻⁴ as measured by tracer dilution technique during hyperinsulinemic-euglycemic clamps in young (○) and old (□) rats exposed to 0, 2, 4, or 6 weeks of caloric restriction. Dashed lines in each panel represent the values from control rats for each parameter for comparison. Data are means ± SEMs. Statistical significance was determined using two-way ANOVAs for the effect of time and age with post hoc Tukey tests for individual comparisons. *P < 0.05 for young vs. week 0 and old vs. week 0; §P < 0.05 young vs. old.

FIG. 4.

Dependency of insulin sensitivity on abdominal fat depot size. The correlation among epididymal (A), perirenal (B), and mesenteric fat (C) normalized to body weight vs. insulin resistance (1/whole-body S_I) in all young and old rats used in the study. Correlations are determined for all young and all old rats using the general linear model. A significant difference between young and old slopes was only found for the mesenteric fat depot, and thus visceral fat. Y, young; O, old; m, slope.

FIG. 5.

Circulating adipokine and liver triglyceride content. Plasma levels of adiponectin (A), resistin (B), leptin (C), and lipid content (D) in liver in young and old rats exposed to 0, 2, 4, or 6 weeks of caloric restriction. Data are means ± SEMs. Statistical significance was determined using two-way ANOVAs for the effect of time and age with post hoc Tukey tests for individual comparisons. *P < 0.05 for young vs. week 0 and old vs. week 0; §P < 0.05 young vs. old.