Older Animals Are Refractory to Improved Insulin Sensitivity During Weight Loss, Despite Preferential Reduction in Abdominal Fat.

It has been suggested that insulin resistance associated with normal aging is caused by a concomitant increase in visceral adipose mass. Previously, we presented data indicating that old animals may in fact have a greater susceptibility to abdominal adipose-induced insulin resistance as compared to young. We asked whether older animals are more at risk for insulin resistance due to central and/or peripheral adiposity by examining young and old rats under conditions of weight loss. Young (Y: 6 mos, n=34) high-fat-fed (3 weeks; 66% calories from fat) and old (O: 24 mos, n=35) obese male Fisher 344xBN rats were subjected to 0, 2, 4, or 6 weeks of caloric restriction (CR; 40% reduction in ad libitum calories). Insulin sensitivity (S[sub 1]) was assessed by euglycemic hyperinsulinemic (5mU/min per kg) clamp following a 6 hour fast. To determine body composition, a bolus of [sup 18]O-water (0.5g/kg BW) was administered to discern total body water and reveal lean body mass (LBM) and total body fat. Also, abdominal (AB) fat depots (epididymal, perirenal and mesenteric) were excised and weighed at necropsy to determine both AB and SubQ fat mass. Six weeks of CR caused a mild, but significant reduction in body weight in both Y and O animals (Y: ↓ 12.96±1.3%; O: ↓ 13.77±2.1%; p<0.05 by ANOVA), and was similar for both age groups (p=0.748). Surprisingly, this change in body weight was not due to a decline in SubQ fat (0 vs 6 wks for Y: p=0.629; O: p=0.370) or LBM (0 vs 6 wks for Y: p=0.641; O: p=0.257). In stark contrast, significant toss occurred in the AB fat depot (Y: ↓ 46.43±1.7%; O: ↓ 28.51±4.6%; p<0.05 by ANOVA). Most notably, mesenteric fat, the only true visceral fat depot in the rodent, was reduced equivalently in Y (↓ 52.70±2.53 %) and O (↓ 52.63±4.09%) rats with 6 weeks of CR (Y vs. O p=0.537). Despite strikingly similar losses in visceral fat in Y and O rats, S[sub I] improved to a lesser extent in O rats (↑ 32.76±9.80%) compared to Y (↑ 82.91±12.66%) when compared to 0 weeks. Comparison of regression analyses for these data further demonstrated that for a given loss of visceral fat mass, O rats exhibited less improvement in S[sub I] (p<0.0001). In conclusion, subcutaneous fat can not account for improvements in insulin sensitivity; rather these data demonstrate a preferential loss of fat in the abdominal depot with short-term diet restriction in both old and young animals. Furthermore, old rats have an increased susceptibility to abdominal-fat induced insulin resistance. The mechanism of this increased risk in older animals to obesity remains unclear. [ABSTRACT FROM AUTHOR]