Specific subpopulations of hypothalamic leptin receptor-expressing neurons mediate the effects of early developmental leptin receptor deletion on energy balance

Alan C Rupp,Margaret B Allison,Justin C Jones,Christa M Patterson,Chelsea L Faber,Nadejda Bozadjieva,Lora K Heisler,Randy J Seeley,David P Olson,Martin G Myers

doi:10.1016/j.molmet.2018.06.001

Alan C Rupp, Margaret B Allison + Show 8 more

Open Access

https://doi.org/10.1016/j.molmet.2018.06.001

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Abstract

ObjectiveTo date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons (e.g., arcuate nucleus (ARC) Pomc- or Agrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolic dysfunction. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance. MethodsWe generated new mouse lines deleted for LepRb in ARC GhrhCre neurons or in Htr2cCre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells. ResultsThe early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc, Agrp, Ghrh, or Htr2c neurons minimally altered energy balance. ConclusionsAlthough early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH.

Highlights

Obesity, which affects more than 1/3 of people in developed countries, predisposes to diabetes, cardiovascular disease, and other serious comorbidities [1]
Conclusions: early developmental deletion of LepRb from known populations of arcuate nucleus (ARC) neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental
LepRb neurons must play important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the dorsomedial hypothalamus (DMH)

Summary

Introduction

Obesity, which affects more than 1/3 of people in developed countries, predisposes to diabetes, cardiovascular disease, and other serious comorbidities [1]. To design effective treatments for obesity, we must first understand the systems that control energy balance and which represent potential therapeutic targets. The hormone leptin, which is produced by adipose tissue to signal the repletion of fat stores, acts via its receptor (LepRb) on hypothalamic neurons to suppress food intake and permit energy expenditure [2]. Leptin- or LepRb-deficient humans and rodent models display dramatic hyperphagia and reduced energy expenditure, leading to severe obesity [3e5]. The hypothalamic neurons by which leptin mediates the control of energy balance represent important controllers of energy balance. Hypothalamic LepRb neurons Within the hypothalamus, the arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMN), dorsomedial hypothalamus (DMH), lateral hypothalamic area (LHA), and ventral premammillary nucleus (PMv) contain substantial numbers of LepRb neurons [6]. While orexigenic ARC neurons that contain agouti-

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