The hypothalamus as the central regulator of energy balance and its impact on current and future obesity treatments

Abstract

The hypothalamus is a master regulator of energy balance in the body. First-order hypothalamic neurons localized in the arcuate nucleus sense systemic signals that indicate the energy stores in the body. Through distinct projections, arcuate nucleus neurons communicate with second-order neurons, which are mostly localized in the paraventricular nucleus and in the lateral hypothalamus. The signals then proceed to third- and fourth-order neurons that activate complex responses aimed at maintaining whole-body energy homeostasis. During the last 30 years, since the identification of leptin in 1994, there has been a great advance in the unveiling of the hypothalamic and extra-hypothalamic neuronal networks that control energy balance. This has contributed to the characterization of the mechanisms by which glucagon-like peptide-1 receptor agonists promote body mass reduction and has opened new windows of opportunity for the development of drugs to treat obesity. This review presents an overview of the mechanisms involved in the hypothalamic regulation of energy balance and discusses how advancements in this field are contributing to the development of new pharmacological strategies to treat obesity.

Keywords: Food intake; POMC; adipose tissue; brain; neuron; proopiomelanocortin.

Figure 1. Schematic illustration of the main abnormalities in the hypothalamus in obesity. According to experimental studies, it has been shown that the consumption of excessive dietary fats and, to a lesser extent, excessive dietary sugars can promote hypothalamic microgliosis, inflammation, abnormal regulation of autophagy, and proteostasis, leading to defective function and, eventually, apoptosis of hypothalamic neurons involved in whole-body energy balance. In humans, evidence is based on neuroimaging studies, therefore, it is currently uncertain whether all these abnormalities exist. Thus, this schematic figure is illustrative.