Regulation of Food Intake and Gonadotropin-Releasing Hormone/Luteinizing Hormone during Lactation: Role of Insulin and Leptin

Abstract

Negative energy balance during lactation is reflected by low levels of insulin and leptin and is associated with chronic hyperphagia and suppressed GnRH/LH activity. We studied whether restoration of insulin and/or leptin to physiological levels would reverse the lactation-associated hyperphagia, changes in hypothalamic neuropeptide expression [increased neuropeptide Y (NPY) and agouti-related protein (AGRP) and decreased proopiomelanocortin (POMC), kisspeptin (Kiss1), and neurokinin B (NKB)] and suppression of LH. Ovariectomized lactating rats (eight pups) were treated for 48 h with sc minipumps containing saline, human insulin, or rat leptin. The arcuate nucleus (ARH) was analyzed for NPY, AGRP, POMC, Kiss1, and NKB mRNA expression; the dorsal medial hypothalamus (DMH) was analyzed for NPY mRNA. Insulin replacement reversed the increase in ARH NPY/AGRP mRNAs, partially recovered POMC, but had no effect on recovering Kiss1/NKB. Leptin replacement only affected POMC, which was fully recovered. Insulin/leptin dual replacement had similar effects as insulin replacement alone but with a slight increase in Kiss1/NKB. The lactation-induced increase in DMH NPY was unchanged after treatments. Restoration of insulin and/or leptin had no effect on food intake, body weight, serum glucose or serum LH. These results suggest that the negative energy balance of lactation is not required for the hyperphagic drive, although it is involved in the orexigenic changes in the ARH. The chronic hyperphagia of lactation is most likely sustained by the induction of NPY in the DMH. The negative energy balance also does not appear to be a necessary prerequisite for the suppression of GnRH/LH activity.

Kisspeptin and energy balance in reproduction

“…In order to examine the mechanisms underpinning hyperphagia in genetically obese and infertile ob/ob mice, Wu et al (2012) discovered that ablating NPY/AgRP neurons in these mice caused a prolonged period of reduced food intake and remarkably restored fertility in both males and females. Consistent with this is the inhibitory effect of NPY on GNRH/LH secretion (Barker-Gibb et al 1995, Xu et al 2009). Interestingly, NPY may inhibit or stimulate LH secretion according to the steroid milieu in rats, inhibiting in OVX models, but stimulating in intact (Kalra & Crowley 1984).…”

Food restriction during lactation suppresses Kiss1 mRNA expression and kisspeptin-stimulated LH release in rats

“…Estradiol stimulates Kiss1 mRNA expression in the AVPV and suppresses Kiss1 mRNA expression in the arcuate nucleus . Arcuate nucleus Kiss1 mRNA expression has been shown to be suppressed during early and mid lactation (Yamada et al 2007, Xu et al 2009, True et al 2011, while AVPV Kiss1 mRNA is either unchanged (Yamada et al 2007) or decreased (True et al 2011). These data suggest that a decrease in kisspeptin expression might underlie the loss of fertility during lactation.…”

Limits to sustained energy intake. XVII. Lactation performance in MF1 mice is not programmed by fetal number during pregnancy

“…A reduction in circulating leptin may have facilitated the rapid elevation in intake in the large litter size group during the early phase of lactation. Manipulations of leptin in lactation, however, have yielded ambiguous results, with some studies showing reduced intake in response to repletion of leptin levels (Cui et al, 2010;Stocker et al, 2007) but others showing no effect (Xu et al, 2009), so the importance of this effect is unclear. Second, lowered fat, in combination with lowered pelage mass, might aid heat dissipation capacity and modulate the hypothesised heat dissipation constraint on intake (Speakman and Król, 2010;Speakman and Król, 2011).…”