Bal Anand and John Brobeck and the Hypothalamic Control of Eating (II)
ANAND B.K., BROBECK, J.R.
Hypothalamic control of food intake in rats and cats. Yale Journal of Biology and Medicine 24: 123-140; 1951..
Comment by Tim Moran (March, 2014)
Hetherington and Ranson had demonstrated that stereotaxic lesions of the ventromedial hypothalamus (VMH) resulted in obesity . John Brobeck, a young physiologist at Yale University, soon after established a research program examining the mechanisms underlying the effects of such lesions and their relationships with food intake, energy metabolism and temperature regulation [see SSIB Ingestive Classic 5]. In 1951, he was joined by Bal Krishan Anand, a young Indian MD who had been awarded a postdoctoral training fellowship from the Rockefeller Foundation. Brobeck started Anand out with a group of rats and the task of replicating the effects of ventromedial hypothalamic lesions. Using the Horsley-Clarke stereotaxic device as adapted by Clarke for use in the rat , Anand repeated the lesion procedure but obtained the opposite result –instead of hyperphagia and obesity, the rats completely stopped eating, lost weight and eventually died. Rather than simply disregarding the findings, Anand and Brobeck carefully examined the histology to identify the location of the lesions and found that rather than focal lesions, Anand had produced large lesions that extended well beyond the extent of the VMH. It turns out that there was a defect in the lesion-making instrument resulting in the passage of significantly more current than desired and the production of the larger lesions .
This initial serendipitous finding served as the basis for a systematic examination of the effects of altering hypothalamic lesion size and location on food intake and body weight in both rats and cats, which Anand and Brobeck described in their classic 1951 paper, Hypothalamic Control of Food Intake in Rats and Cats in the Yale Journal of Biology and Medicine . The running head of the article, Hypothalamic Feeding Centers, is appropriate as they demonstrated that the basis for the initial result from the large lesions was the destruction of the lateral hypothalamus (LH), which they termed the “feeding center”.
The paper has a number of important components. Consistent with their pilot findings, they demonstrated that large hypothalamic lesions that destroyed both the VMH and LH resulted in aphagia and eventual death and that this experimental endpoint was also produced by small bilateral lesions of the LH at the rostral-caudal level of the VMH. LH lesions that were either rostral or caudal to the VMH resulted in reduced food intake for a day or two followed by a complete return to normal food intake and growth rate. This finding led Anand and Brobeck to conclude that while the critical region of the LH contained many fibers of passage, the aphagia was not simply the result of disconnection but derived from the destruction of a local neuronal population.
They demonstrated that unilateral LH lesions did not affect food intake, making the points that this was consistent with the ineffectiveness of unilateral VMH lesions and demonstrations that stimulation of either side of the hypothalamus usually affects both sides of the visceral nervous system.
Making bilateral LH lesions in rats that had been rendered hyperphagic and obese through prior VMH lesions resulted in immediate aphagia, while making VMH lesions in rats that were aphagic due to LH lesions did not stimulate feeding. Anand and Brobeck interpreted these results as indicating that he LH was a feeding center that was tonically active and was inhibited by inputs from the VMH. The size of VMH lesions made a difference, as small lesions resulted in less hyperphagia and obesity than did large lesions, a result interpreted as a difference due to the amount of inhibitory output that was interrupted by the lesion.
Enthusiasm for a role for the LH in feeding control waxed and waned over the years. The outcomes of VMH and LH lesions combined with Anand’s own demonstration of the ability LH electrical stimulation to stimulate food intake  served as the basis for Eliot Stellar’s influential review on the Physiology of Motivation, in which he argues for dual satiety and feeding centers within the hypothalamus . Ungerstedt’s work with lesions of ascending dopaminergic pathways turned attention away from intrinsic LH neurons and onto ascending pathways traveling though this region , leading to the extensive work on the role of dopaminergic fibers in the medial forebrain bundle in reward . However, excitotoxic lesions localized to the LH and sparing fibers of passage confirmed important local LH actions in the control of food intake [7, 13, 15], and more recent work identifying neuronal populations expressing orexigenic peptides within the LH have confirmed the importance of this region in feeding control [10, 11].
The identification of neuronal populations expressing orexigenic and anorexigenic peptides within the arcuate nucleus has shifted the focus away from the VMH and onto the arcuate nucleus as the critical ventral medial hypothalamic nucleus in feeding control. However, recent work demonstrating that specific deletion of leptin receptors in SF-1 expressing neurons within the VMH results in hyperphagia and obesity confirms an important role for the VMH in controlling food intake and energy balance [2, 6].
Both Anand and Brobeck continued to work on the controls of food intake and energy balance throughout their careers. John Brobeck went on to be the long-time chair of Physiology at the University of Pennsylvania School of Medicine and was the inaugural recipient of the SSIB Distinguished Career Award at the initial meeting in Princeton. B.K. Anand returned to India, and had an illustrious career as head of Physiology at the All India Institute of Medical Sciences.
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