Abstract
Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.
Highlights
The mechanisms by which warm-blooded animals balance energy intake with energy expenditure have come under increasing scrutiny in recent years
These results correspond to what has been described previously for normal development of the melanocortinergic system, with the hypothalamic Pomc system becoming established during fetal brain development, but the agouti-related protein (Agrp) system developing after birth [19,20]
Physical or chemical lesioning studies carried out 60 years ago first drew attention to the ventromedial area and the lateral hypothalamic area of the hypothalamus as sites important for regulating energy balance [23,24], functional heterogeneity within the arcuate nucleus of the hypothalamus was not recognized until recently
Summary
The mechanisms by which warm-blooded animals balance energy intake with energy expenditure have come under increasing scrutiny in recent years. Important components of this process are the changes associated with aging. As part of the normal aging process, a slow but progressive increase in adiposity occurs throughout most of adulthood (reviewed in [1,2]) In both humans and rodents, these changes occur independently of environmental variation, and are likely to be caused by the progressive impairment of mechanisms that normally control energy homeostasis [3,4,5]. Pomc and Agrp neurons integrate and relay this information to downstream central nervous system effectors that act to balance energy stores via changes in both energy intake and expenditure, with activation of Pomc neurons promoting negative energy balance, and activation of Agrp neurons promoting positive energy balance [8,9]
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