Endoplasmic Reticulum Stress, the Hypothalamus, and Energy Balance

The obese state induces cellular and metabolic alterations in the hypothalamus, leading to chronic low-grade inflammation and ER stress that, in turn, alters energy balance. ER membrane-resident sensors transmit ER stress signals to the cell through signaling routes collectively called the unfolded protein response (UPR). The UPR pathways act in concert to increase ER content, expand ER protein-folding capacity, degrade misfolded proteins, and reduce the load of new proteins entering the ER. All of these are geared toward adaptation to resolve the protein-folding defect. The hypothalamic ER stress acts to favor a positive energy balance, attenuating the response to the anorectic hormone leptin. Processing of the hypothalamic POMC is impaired by obesity-induced ER stress, leading to decreased production of α-MSH, a central regulator of energy homeostasis. Overweight and obesity pose significant health problems globally, and are causatively linked to metabolic dysregulation. The hypothalamus integrates neural, nutritional, and hormonal cues to regulate homeostasis, including circadian rhythm, body temperature, thirst, food intake, energy expenditure, and glucose metabolism. Hypothalamic neuropeptides play a fundamental role in these processes. Studies during the past two decades suggest a role of central endoplasmic reticulum (ER) stress in the pathophysiology of obesity. This review covers recent findings on the role of ER stress and neuropeptide processing in the central regulation of energy homeostasis, with special emphasis on proopiomelanocortin (POMC)-encoding neurons. In addition, the role of neuroinflammation in the context of obesity is briefly discussed. Overweight and obesity pose significant health problems globally, and are causatively linked to metabolic dysregulation. The hypothalamus integrates neural, nutritional, and hormonal cues to regulate homeostasis, including circadian rhythm, body temperature, thirst, food intake, energy expenditure, and glucose metabolism. Hypothalamic neuropeptides play a fundamental role in these processes. Studies during the past two decades suggest a role of central endoplasmic reticulum (ER) stress in the pathophysiology of obesity. This review covers recent findings on the role of ER stress and neuropeptide processing in the central regulation of energy homeostasis, with special emphasis on proopiomelanocortin (POMC)-encoding neurons. In addition, the role of neuroinflammation in the context of obesity is briefly discussed.