Leptin Action via Neurotensin Neurons Controls Orexin, the Mesolimbic Dopamine System and Energy Balance

Abstract

Summary Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRbNts neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRbNts neurons with local OX neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRbNts neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance.

A leptin-regulated circuit controls glucose mobilization during noxious stimuli

“…Statistical methods were not used to predetermine sample sizes, but our sample sizes are similar to those in previously published studies using similar approaches (8,17,(37)(38)(39). Sample sizes for groups that involved stereotaxic injection of specific populations of cells were 40% larger than for other groups to account for a 50%-60% bilateral hit rate.…”

Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action

“…However, the neuropeptides involved in these leptin actions have not been characterized completely. Within the LH, a subpopulation of LepRb neurons coexpresses neurotensin (37). Our data show that exPFA neurotensin neurons almost entirely coexpressed galanin, although compared with the total number of galanin neurons, neurotensin was found in only a small subset of galanin neurons.…”

“…Within the exPFA, only LH LepRb neurons have been studied in more detail (36,37,40), characterized as the population distal-lateral to the fornix (20,36), thus excluding neurons in the PFA (surrounding the fornix) and DMH (proximal-lateral to the fornix). LH LepRb neurons are sufficient to regulate body weight and food intake in leptin-deficient ob/ob mice.…”

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

“…Thus mice lacking LepRb in SF1-expressing neurons of the VMN develop mild obesity when fed a chow diet and are markedly sensitive to high-fat diet-induced obesity, supporting a role for VMN neurons in leptin's regulatory actions (121). In addition, targeted deletion of LepRb in LHA neurotensin neurons causes early-onset obesity due to hyperphagia and locomotor inactivity (284). Notably, neurotensin neurons appear anatomically well-poised to relay leptin's actions on the mesolimbic dopaminergic system, suggesting that neurotensin neurons may be a crucial point of convergence for homeostatic and hedonic interactions that regulate ingestive behavior.…”