The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight

doi:10.1016/j.physbeh.2005.10.007

Physiology & Behavior

Volume 87, Issue 2, 28 February 2006, Pages 221-244

https://doi.org/10.1016/j.physbeh.2005.10.007 Get rights and content

Abstract

Early researchers found that lesions of the ventromedial hypothalamus (VMH) resulted in hyperphagia and obesity in a variety of species including humans, which led them to designate the VMH as the brain's “satiety center.” Many researchers later dismissed a role for the VMH in feeding behavior when Gold claimed that lesions restricted to the VMH did not result in overeating and that obesity was observed only with lesions or knife cuts that extended beyond the borders of the VMH and damaged or severed the ventral noradrenergic bundle (VNAB) or paraventricular nucleus (PVN). However, anatomical studies done both before and after Gold's study did not replicate his results with lesions, and in nearly every published direct comparison of VMH lesions vs. PVN or VNAB lesions, the group with VMH lesions ate substantially more food and gained twice as much weight. Several other important differences have also been found between VMH and both PVN and VNAB lesion-induced obesity. Concerns regarding (a) motivation to work for food and (b) the effects of nonirritative lesions have also been addressed and answered in many studies. Lesion studies with weanling rats and adult pair-tube-fed rats, as well as recent studies of knockout mice deficient in the orphan nuclear receptor steroidogenic factor 1, indicate that VMH lesion-induced obesity is in large part a metabolic obesity (due to autonomic nervous system disorders) independent of hyperphagia. However, there is ample evidence that the VMH also plays a primary role in feeding behavior. Neuroimaging studies in humans have shown a marked increase in activity in the area of the VMH during feeding. The VMH has a large population of glucoresponsive neurons that dynamically respond to blood glucose levels and numerous histamine, dopamine, serotonin, and GABA neurons that respond to feeding-related stimuli. Recent studies have implicated melanocortins in the VMH regulation of feeding behavior: food intake decreases when arcuate nucleus pro-opiomelanocortin (POMC) neurons activate VMH brain-derived neurotrophic factor (BDNF) neurons. Moderate hyperphagia and obesity have also been observed in female rats with damage to the efferent projections from the posterodorsal amygdala to the VMH. Hypothalamic obesity can result from damage to either the POMC or BDNF neurons. The concept of hypothalamic feeding and satiety centers is outdated and unnecessary, and progress in understanding hypothalamic mechanisms of feeding behavior will be achieved only by appreciating the different types of neural and blood-borne information received by the various nuclei, and then attempting to determine how this information is integrated to obtain a balance between energy intake and energy output.

Introduction

For researchers investigating satiety mechanisms in feeding behavior and body weight regulation, the ventromedial hypothalamus (VMH) was once the center of the universe. Between 1940 and 1980, there were hundreds of published studies of the effects of VMH lesions and stimulation or of knife cuts in and around the VMH. Then, almost as fast as you can say paraventricular hypothalamic nucleus (PVN), the VMH disappeared from many feeding researchers' vocabulary. Today, the VMH is not even included in some leading anatomists' schema of hypothalamic nuclei involved in feeding behavior [101], [312] and is barely mentioned in some reviews of the central (brain) control of feeding behavior (e.g., [352], [415]). Some biopsychology textbooks dismiss a role for the VMH entirely (e.g., [61], [315]). This paper reviews (in chronological order) the rise and fall of the VMH in feeding research, and after addressing the major issues that led to its demise, concludes that dismissal of a role for the VMH in feeding behavior and body weight regulation was premature.

Some researchers use the term ventromedial hypothalamus to refer either to a general area (e.g., [80], [117]) or to the ventromedial hypothalamic nucleus and arcuate nucleus (ARC) combined (e.g., [240]). In this paper, VMH refers only to the VMH nucleus, its capsule (shell), and dendritic branches. When the ARC was purposely included in a study, or the target (of lesions or stimulation) was not the VMH nucleus itself but instead was the basomedial hypothalamus (i.e., the ventral and medial portion of the hypothalamus, hereafter referred to as the VMH area), that will be specifically indicated. The abbreviation “VMH” (rather than VMN) follows the nomenclature of the widely used stereotaxic atlas by Paxinos and Watson [310].

Section snippets

Fröhlich's syndrome and early experimental studies

An obesity syndrome in humans that was associated with abnormalities of the basomedial hypothalamus was reported as early as 1840 [277]. This was initially attributed to endocrine imbalances due to dysfunction of the pituitary gland [17], [124] and eventually came to be known as Fröhlich's syndrome. The belief that the obesity was due to pituitary dysfunction remained the prevailing view through the mid-1930s (e.g., [25], [82], [104], [195]).

The first challenge to the idea that Fröhlich's

The fall

Concerns regarding the role of the VMH in feeding behavior had been raised as early as the 1940s (see following discussion). Nevertheless, by 1970, the evidence in favor of the VMH as the brain's satiety center seemed so convincing that only a few researchers had challenged it. The fall was rapid. Enough contradictory evidence was obtained in the early 1970s that Richard Gold published a paper in 1974 with the title “Hypothalamic obesity: the myth of the ventromedial nucleus” [134]. An

Metabolic/autonomic disorders

In the late 1960s and afterwards, several groups reported a sex difference with electrolytic or goldthioglucose VMH lesions—female rats and mice gained substantially more weight than males [81], [189], [212], [345], [370], [372], even when gonadectomized first [189] or matched for age and preoperative weight [81]. A similar sex difference has been found for septal lesions [372], [410], posterodorsal amygdaloid lesions [221], stria terminalis transections [334], and intraventricular PCPA

Conclusions

Advances in science depend on replicable results, and to date no study has supported Gold's claim [134] that maximum weight gains following lesions in the basomedial hypothalamus are produced by lesions anterior to the VMH (see [6], [138], [161], [163], [165] for contradictory results). Gold also claimed that lesions restricted to the VMH do not cause overeating or weight gain and that the hyperphagia and weight gain was due instead to damage to the VNAB or PVN. However, several groups reported

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Invited ReviewThe rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight

Abstract

Introduction

Section snippets

Fröhlich's syndrome and early experimental studies

The fall

Metabolic/autonomic disorders

Conclusions

Brain Res

Exp Neurol

Physiol Behav

J Dairy Sci

Physiol Behav

Neurosci Biobehav Rev

Brain Res

Physiol Behav

Physiol Behav

Brain Res Bull

Physiol Behav

Neuropeptides

Physiol Behav

Brain Res

Brain Res

Neuroscience

Brain Res

Pharmacol Biochem Behav

Behav Brain Res

Physiol Behav

Neurosci Lett

Physiol Behav

Overeating and obesity from damage to a noradrenergic system in the brain

Science

Hyperphagia following lesions of the noradrenergic pathway is prevented by hypophysectomy

Fed Proc

Hypothalamic hyperphagia: disssociation from hyperphagia following destruction of noradrenergic neurons

Science

Hyperphagia in rats with cuts between the ventromedial and lateral hypothalamus

Science

Hypothalamic controls of food intake in rats and cats

Yale J Biol Med

Activity of single neurons in the hypothalamic feeding centers: effect of glucose

Am J Physiol

Feeding responses induced by electrical stimulation of the hypothalamus in cat

Indian J Med Res

Hypothalamic control of food intake in cats and monkeys

J Physiol

c-Fos expression in hypothalamic nuclei of food-entrained rats

Am J Physiol

Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes

Behav Neurosci

Anatomical connections between medial and lateral regions of the hypothalamus concerned with food intake

Science

Über die Funktion der Hypophyse

Pflügers Arch Gesamte Physiol

Hyperpahgie et steatose hepatique chez l'oie apres lesion du noyau ventro median de l'hypothalamus

C R Acad Sci Paris Ser D Sci Nat

Tumeur du corps pituitaire, sans acromégalie, et avec arrêt de développement des organs géniteaux

Rev Neurol

Anatomy of an endogenous antagonist: relationship between agouti-related protein and proopiomelanocortin in brain

J Neurosci

Experimental diabetes insipidus

Arch Intern Med

Feeding patterns of normal and ventromedial hypothalamic lesioned male and female rats

J Comp Physiol Psychol

Leptin receptor in mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus

Diabetes

Inhibitory controls of feeding by the ventromedial hypothalamus

Am J Physiol

Disruption of arcuate/paraventricular nucleus connections changes body energy balance and response to acute stress

J Neurosci

Experimental operation on the pituitary

Q J Exp Physiol

Effect of ventromedial and dorsomedial hypothalamic lesions on circadian corticosterone levels

Neuroendocrinology

Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin

Endocrinology

Production of weanling rat ventromedial and dorsomedial hypothalamic syndromes by electrolytic lesions with platinum–iridium electrodes

Neuroendocrinology

Effects of hypothalamic lesions at different loci in development of hyperinsulinemia and obesity in the weanling rat

J Comp Neurol

Invited Review
The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight