Leptin and the systems neuroscience of meal size control

Abstract

The development of effective pharmacotherapy for obesity will benefit from a more complete understanding of the neural pathways and the neurochemical signals whose actions result in the reduction of the size of meals. This review examines the neural control of meal size and the integration of two principal sources of that control – satiation signals arising from the gastrointestinal tract and CNS leptin signaling. Four types of integrations that are central to the control of meal size are described and each involves the neurons of the nucleus tractus solitarius (NTS) in the dorsal hindbrain. Data discussed show that NTS neurons integrate information arising from: (1) ascending GI-derived vagal afferent projections, (2) descending neuropeptidergic projections from leptin-activated arcuate and paraventricular nucleus neurons, (3) leptin signaling in NTS neurons themselves and (4) melanocortinergic projections from NTS and hypothalamic POMC neurons to NTS neurons and melanocortinergic modulation of vagal afferent nerve terminals that are presynaptic to NTS neurons.

Introduction

The dramatic increase in the prevalence of obese and overweight individuals over the past two decades has intensified interest in obesity (and its co-morbidities – type II diabetes mellitus, cardiovascular disease, and certain cancers) and the need for additional research on its mediating mechanisms. The “obesity epidemic” is attributed to features of modern life – increased consumption of abundant and palatable energy-dense foods [119], [18] and reduced physical activity [58] – that interact with an energy balance regulatory system that evolved in response to food scarcity [87], [88], [135]. Despite the increased prevalence of obesity in adult and pediatric populations, and an appreciation of the enormous economic and personal costs of treating obesity and its co-morbidities, there are presently no pharmacological treatments that curtail excess feeding and yield meaningful sustained weight loss. The failure to identify effective drug treatments for obesity is, of course, unrelated to the significant scientific effort and economic investment by the government (see NIH Strategic Plan for Obesity Research) and by the pharmaceutical industry. In fact, by targeting the regulatory neural systems governing energy balance at a cellular level, basic science has succeeded in identifying critical roles for novel hormones (leptin, glucagon-like peptide-1, ghrelin), neuropeptides (melanocortin, melanin-concentrating hormone), and other neurochemicals (serotonin, dopamine, opioids and cannabinoids), as well as their respective receptors in energy balance regulation [10], [2], [69], [42], [109], [44], [144], [133], [141], [160].

A likely explanation for the absence of effective drug treatments can be found in the multi-determined nature of an energy balance control system that evolved under pressures of food scarcity. Physiologic systems are confronted with a difficult problem – how to maintain supplies of the energy-rich molecules that are in constant demand to power the myriad cellular processes necessary for survival and reproduction. It appears that our energy balance regulatory systems “solved” the problem of chronic energy demand by evolving multiple and, in some instances, redundant sub-systems. A neuroendocrine system that employs multiple signals, receptors, and brain circuits that operate with a degree of redundancy would appear to be better able to ensure that adequate energy is available to power the demands of survival and reproduction than a CNS control system centered in a single brain site using fewer feedback signals. As food scarcity was the prevailing condition during our ancestral development and food abundance occurred only periodically, the regulatory systems of our Paleolithic ancestors performed well [87], [88], [135] – matching energy intake (feeding behavior) with energy expenditure in most individuals [58]. Historically, obesity was uncommon under those conditions. But, in recent decades the food availability and energy expenditure demands of our environment have changed dramatically. The development of agribusiness with support from government provides abundant quantities of low-cost, energy-dense foods [110] that, given the bias of our regulatory system towards consumption during periods of food availability [126], appears to promote a state of chronic hyperphagia that drives positive energy balance, increased adiposity, and ultimately obesity in many individuals.

The problem at hand then is the need to develop effective and safe pharmacological treatments for obesity (radical surgical treatment is effective but has associated risks). This task leads us to an in-depth consideration of the brain mechanisms responsible for the inhibition of food intake in the non-obese state. Humans and many other mammals (including common laboratory rodent models) consume food in discrete episodes or meals. Distinguishable behavioral responses are controlled by various brain regions and neurochemical systems that impact on various aspects of meal taking, including the initiation, size, and frequency of meals. Given the aforementioned abundant food environment, the initiation of meals, for most of us, is not associated with hunger (homeostatic need, negative energy balance or the absence of gastrointestinal satiation signals). Rather, meal initiation for many people is based on appetite – the time of day, the constraints of our schedules, social circumstances, the hedonic allure of foods (referred to as reward or food-reward), and learned associations [153], [138], [89], [154]. These contributory factors to meal initiation are considered non-homeostatic (not driven by energy deficit). While their contribution to the control of feeding and the obesity epidemic is clear, our current understanding of the neurons, signaling cascades, neural circuits and neurochemicals that mediate their biological influences on feeding is poorly developed. By contrast, the physiological underpinnings of the factors that control meal termination and thereby meal size (the amount of food consumed during a meal) has been more extensively studied.

G.P. Smith distinguishes between two categories of signals that contribute to the control of meal size [134]. He uses the term direct controls of meal size, to describe signals arising from the alimentary canal in response to contact with ingested food or to the products of its digestion. Direct controls, more commonly referred to as satiation signals, include sensory signals arising from the interaction of ingested food with the gastrointestinal (GI) tract and include mechanical distension of the stomach, nutrient stimulation of the intestine, and intestinal hormones released in response to calorie-bearing nutrients (e.g., cholecystokinin [CCK], glucagon-like peptide-1 [GLP-1], peptide YY 3-36 [PYY3-36]) [96]. It is well known that these satiation signals activate receptors on vagal afferent neurons whose cell bodies reside in the nodose ganglion and whose central processes terminate on neurons of specified subnuclear regions of the nucleus tractus solitarius (NTS) [111], [113], [14], [71]. NTS neurons project to many other neurons throughout the neuraxis including those in the pons (parabrachial nucleus, PBN), hypothalamus (lateral hypothalamus, LH; paraventricular nucleus, PVH), basal forebrain (bed nucleus of stria terminalis; central nucleus of the amygdala), thalamus, and agranular insular cortex. This projection system is referred to as the ascending central visceral afferent pathway [90], [121].

Smith [134] and others (e.g. Berthoud et al. [16]; Woods et al. [155]) agree that meal size is influenced by other types of signals including metabolic signals (fuel availability), such as circulating levels of nutrients (e.g. glucose, free fatty acids and amino acids). In addition, correlates of stored energy commonly referred to as adiposity signals (leptin, insulin), rhythmic signals (cyclic sex hormones such as estrogen, diurnal or circadian signals), and signals associated with conditioning, environmental temperature, or ecology contribute to meal size control. Smith parts company with others considering the control of meal size by his creation of a separate category for these signals and refers to them as indirect controls [116]. The “indirect” designation is employed to contrast with “direct” and to define a specific relationship between the mechanism of effect for these signals and the neural processing of the satiation signals arising from direct contact of ingested food within the GI tract. Smith describes the intake inhibitory impact of these signals as indirect because he views their action as modulating or amplifying the neural processing of direct (a.k.a. satiation) signals as opposed to their having an independent behavioral action of their own. This idea is empirically generative as it suggests experiments that may better define the neural pathways and signaling cascades that control the termination of feeding behavior and perhaps by so doing, these notions may inform the selection of new drugs to more effectively treat obesity. The balance of this article explores the neural pathways and the neurochemical signals that mediate the food intake inhibitory actions of satiation signals and the interaction between adiposity signals and satiation signals.