Elsevier

Physiology & Behavior

Volume 74, Issues 4–5, 12 November 2001, Pages 703-708
Physiology & Behavior

Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin

https://doi.org/10.1016/S0031-9384(01)00613-8Get rights and content

Abstract

Leptin affects feeding, metabolism, and neuroendocrine status. It is now clearly established that the hypothalamus coordinates these responses, though the specific brain regions engaged by leptin remain unclear. We have used combinations of neuroanatomic techniques to identify candidate pathways in the central nervous system underlying leptin action. Leptin decreases body weight in part by activating the sympathetic nervous system, resulting in increased thermogenesis and energy expenditure. We investigated hypothalamic pathways underlying leptin's effects on stimulating the sympathetic nervous system. We found that leptin activates neurons in the retrochiasmatic area (RCA) and lateral arcuate nucleus (Arc) that innervate the sympathetic preganglionic neurons in the thoracic spinal cord and also contain cocaine- and amphetamine-regulated transcript (CART). We also found that CART neurons in the RCA and the Arc coexpress pro-opiomelanocortin (POMC) mRNA. Recent studies have reinforced the view that the lateral hypothalamic area (LHA) regulates food intake and body weight. Using retrograde tracing with leptin administration, we found retrogradely labeled cells in the Arc contained neuropeptide Y (NPY) mRNA or POMC mRNA. Following leptin administration, NPY cells in the Arc did not express Fos but expressed suppressor of cytokine signaling-3 (SOCS-3) mRNA. In contrast, leptin induced both Fos and SOCS-3 expression in POMC neurons, many of which also innervated the LHA. We suggest that leptin directly activates POMC/CART neurons that project to the LHA, the paraventricular hypothalamic nucleus (PVH), and spinal sympathetic preganglionic neurons. These projections link circulating leptin and neurons that regulate feeding behavior, energy expenditure, and body weight homeostasis.

Introduction

The identification of the ob gene by positional cloning in 1994 led to a dramatic increase in the understanding of the molecular control of metabolism and body weight [1]. Leptin, the product of the ob gene, is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis, and neuroendocrine responses [2], [3], [4], [5], [6]. The severe obesity caused by leptin absence in rodents and humans makes it clear that leptin is a fundamental hormone regulating energy homeostasis. It is now established that the hypothalamus integrates leptin signals into a coordinated endocrine, behavioral, and autonomic responses that maintain homeostasis. This report will describe central neural circuits that are downstream of leptin receptors and will propose a model linking populations of leptin-responsive neurons with populations of neurons that underlie leptin's endocrine, autonomic, and behavioral effects.

Section snippets

Distributions of leptin receptors

Several splice variants of the leptin receptor (OB-R) exist. The predominant form is the “short form” and is widely expressed in multiple tissues including the brain [7]. Another splice variant encodes a protein with a longer cytoplasmic domain (OB-Rb) and is often referred to as the “long form” of the receptor. This form is highly expressed in the hypothalamus [8], [9], [10], [11]. Mutations of this protein result in the obese phenotype of the db/db mouse and the Zucker rat, demonstrating that

Leptin-responsive cell groups

The distribution of leptin receptors in the hypothalamus suggests that signaling via these receptors underlies leptin's physiological effects. We and other groups investigated the induction of immediate early genes by leptin in specific nuclear groups. We first used expression of c-fos as a generic marker of neuronal activation. We found that intravenous administration of leptin to fed rats activates several nuclear groups in the rat brain including the ventromedial, dorsomedial, and

Leptin activates neurons innervating the PVH

The effects of leptin on several neuroendocrine systems including the hypothalamo–pituitary–adrenal (HPA) and thyroid axes suggests the PVH is involved in mediating several of the effects of circulating leptin. The PVH is ideally positioned to regulate responses during periods of changing energy availability as it possesses chemically and anatomically specific projections to autonomic and endocrine control sites involved in maintenance of homeostasis (reviewed in [30], [31]).

In our initial

Arc CART neurons respond to leptin

The importance of the melanocortin systems in regulating feeding is now recognized due to recent experimental evidence. For example, targeted deletion of the melanocortin 4 receptor (MC4-R) gene results in obesity [33]. The CNS agonist of MC4-Rs is α-MSH, a derivative of the POMC precursor [34]. Neurons expressing α-MSH are found in the lateral part of the Arc [35]. Additionally, leptin receptor mRNA is coexpressed in a very high percentage of arcuate and POMC neurons [36]. Furthermore, in

Connecting the Arc with the lateral hypothalamus

Multiple pathways are engaged by circulating leptin to regulate food intake. Included in this are likely diffusely projecting pathways that innervate the cerebral cortex that play a role in the complex regulation of feeding behavior and hunger. An attractive candidate for this link is the LHA. The LHA has long been considered a region regulating food intake as lesions of this region can result in decreased food intake and body weight [5]. The LHA contains neurons that innervate the entire

Conclusions

The molecular basis for several obesity syndromes are now understood. It is clear that leptin interacts with hypothalamic systems to regulate endocrine and autonomic function. CART and POMC are coexpressed in the Arc of the hypothalamus and represent anorectic neuropeptides that are positively regulated by leptin. Medial arcuate NPY/AgRP neurons are negatively regulated by leptin. Both populations of arcuate neurons provide a major source of input to the PVH and the lateral hypothalamic MCH and

Acknowledgements

This work was supported in part by USPHS grants DK53301 and DK56149 and support from Eli Lilly.

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