Large litter rearing enhances leptin sensitivity and protects selectively bred diet-induced obese rats from becoming obese

Abstract

Because rearing rats in large litters (LLs) protects them from becoming obese, we postulated that LL rearing would protect rats selectively bred to develop diet-induced obesity (DIO) from becoming obese by overcoming their inborn central leptin resistance. Male and female DIO rats were raised in normal litters (NLs; 10 pups/dam) or LLs (16 pups/dam) and assessed for anatomical, biochemical, and functional aspects of leptin sensitivity at various ages when fed low-fat chow or a 31% fat high-energy (HE) diet. LL rearing reduced plasma leptin levels by postnatal day 2 (P2) and body weight gain by P8. At P16, LL DIO neonates had increased arcuate nucleus (ARC) binding of leptin to its extracellular receptors and at P28 an associated increase of their agouti-related peptide and alpha-MSH axonal projections to the paraventricular nucleus. Reduced body weight persisted and was associated with increased ARC leptin receptor binding and sensitivity to the anorectic effects of leptin, reduced adiposity, and enhanced insulin sensitivity in LL DIO rats fed chow until 10 wk of age. The enhanced ARC leptin receptor binding and reduced adiposity of LL DIO rats persisted after an additional 5 wk on the HE diet. Female LL DIO rats had similar reductions in weight gain on both chow and HE diet vs. normal litter DIO rats. We postulate that LL rearing enhances DIO leptin sensitivity by lowering plasma leptin levels and thereby increasing leptin receptor availability and that this both enhances the ARC-paraventricular nucleus pathway development and protects them from becoming obese.

Figure 1

A, Dam body weight gain during gestation and lactation. B, Dam food intake during lactation. C, Male pup body weight gain from P2–14. D, Male pup plasma leptin levels during dark (D) and light (L) phases from P2 to P14. *, P ≤ 0.05 by repeated-measures ANOVA followed by post hoc t test.

Figure 2

Binding of ¹²⁵I-leptin to its receptors in the ARC of male offspring raised in LLs vs. NL at P16, at 10 wk of age in offspring fed chow from weaning and in offspring fed chow for 10 wk and then the HE diet for an additional 4 wk. *, P ≤ 0.05, LLs vs. NLs by unpaired t test.

Figure 3

Examples of the relative densities of AgRP and α-MSH-immunoreactive fibers (α-MSH-IR) in the paraventricular nuclei (PVH) of male DIO pups raised in NLs vs. those from P28 pups raised in LLs (left panels). V3, Third ventricle. **, P = 0.01, LLs vs. NLs by unpaired t test for comparisons of quantitation of fiber densities.

Figure 4

A, Body weight gain for male rats raised in NLs and LLs and fed chow from weaning until 10 wk of age. *, P ≤ 0.05 when groups were compared by repeated-measures ANOVA followed by post hoc t test. Four-hour (B) and 24-h (C) food intake for NL and LL offspring injected with saline (Sal) or leptin (Lep; 5 mg/kg, ip) are shown. Groups in each panel that differ from each other by P ≤ 0.05 have differing superscript letters.

Figure 5

Body weight gain (A) and food intake over 4 wk on the HE diet in male NL and LL offspring, which had previously been fed chow from weaning until 10 wk of age. *, P ≤ 0.05 by repeated-measures ANOVA followed by post hoc t test.

Figure 6

Body weight gain in NL and LL female offspring fed the HE diet for 5 wk after being fed chow for 10 wk from weaning. Groups that differ from each other by P ≤ 0.05 have different letters.