Abstract
The lateral hypothalamus (LHA) is a central hub in the regulation of food intake and metabolism, as it integrates homeostatic and hedonic circuits. During early development, maturing input to and output from the LHA might be particularly sensitive to environmental dietary changes. We examined the effects of a maternal high fat diet (HFD, 60% Kcal in fat) on the density of hypothalamic projections to the orexin (ORX-A) field of the LHA in 10 day-old (PND10) rat pups using retrograde labeling with fluorescent microspheres. We also compared responsiveness of phenotypically identified LHA neurons to leptin administration (3 mg/kg, bw) between pups from control (CD) or high fat (HFD) fed mothers on PND10 and 15-16, at the onset of independent feeding. HFD pups exhibited a higher density of LHA projections (p = 0.05) from the ventromedial hypothalamus (VMH) compared to CD pups and these originated from both SF-1 and BDNF-positive neurons in the VMH. Increased circulating leptin levels in HFD pups, particularly on PND15-16 was consistent with enhanced pSTAT3 responses to leptin in the orexin (ORX-A) field of the LHA, with some of the activated neurons expressing a GABA, but not CART phenotype. ORX-A neurons colocalizing with pERK were significantly higher in PND15-16 HFD pups compared to CD pups, and leptin-induced increase in pERK signaling was only observed in CD pups. There was no significant effect of leptin on pERK in HFD pups. These results suggest that perinatal maternal high fat feeding increases hypothalamic projections to the ORX-A field of the LHA, increases basal activation of ORX-A neurons and direct responsiveness of LHA neurons to leptin. Since these various LHA neuronal populations project quite heavily to Dopamine (DA) neurons in the ventral tegmental area, they might participate in the early dietary programming of mesocorticolimbic reward circuits and food intake.
Highlights
The lateral hypothalamus (LHA) is central to the regulation of food intake as it integrates incoming metabolic signals from several hypothalamic nuclei with the hedonic regulation of food intake, involving the mesolimbic circuit and in particular, dopamine (DA) activity in the ventral tegmental area (VTA)
The aims of the present study were to determine whether perinatal maternal feeding with a high fat diet (HFD) could modify the establishment of hypothalamic projections to the LHA in neonatal pups and alter the sensitivity of LHA neurons to the metabolic hormone leptin, which is increased by maternal high fat feeding and exerts neurodevelopmental actions in neonatal rodents (Bouret et al, 2004a)
Our results demonstrate that maternal high fat feeding increases the number of ventromedial hypothalamus (VMH) projections to the LHA in pups already by PND10 and increases direct responsiveness of LHA neurons to exogenous leptin administration at the time of onset of independent feeding around PND15-16
Summary
The lateral hypothalamus (LHA) is central to the regulation of food intake as it integrates incoming metabolic signals from several hypothalamic nuclei with the hedonic regulation of food intake, involving the mesolimbic circuit and in particular, dopamine (DA) activity in the ventral tegmental area (VTA). Homeostatic hypothalamic nuclei such as the arcuate nucleus (ARC), ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and hypothalamic paraventricular nucleus (PVN) project either directly or indirectly to the LHA (Hahn and Swanson, 2015) and together with multiple cortical, subcortical and brain stem inputs, regulate LHA activity (Bonnavion et al, 2016). Circulating leptin concentrations in the offspring are significantly increased when mothers are fed a HFD (Trottier et al, 1998)
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