Abstract
The molecular mechanisms involved in the genesis of obesity are extremely relevant for prevention and future treatment of obesity and its comorbidities. The systemic metabolic regulation, in mammals, is orchestrated by neurons located in the hypothalamus. These neurons are able to sense and integrate peripheral signals, which inform the organism its nutritional status. The impairment of anorexigenic signals is a multifactorial event and, in diet induced obesity, is mainly caused by the consumption of saturated fatty acids. Effectively, this impairment is translated into death and malfunctioning of POMC (Pro-opiomelanocortin) expressing neurons, triggered by neuroinflammation. Microglia are resident macrophages in central nervous system and are directly involved in neuroinflammation. Thereby, microglia activation is an essential step in the genesis of obesity. Our data show that alpha-melanocyte stimulating hormone (±-MSH), a neuropeptide derived from POMC neurons, has immunoregulatory roles, acting on microglial cells. Our data indicate that ±-MSH leads to metabolic alterations at cellular levels in microglia, focusing on mitochondrial function. Our aim is to validate our results in human and murine primary microglial culture and determine the roles played by ±-MSH. In detail, we will investigate which melanocortin receptor is most relevant for human and murine cells, and investigate which signaling pathways are involved. The cytokine production and effector function of microglia will also be evaluated upon ±-MSH treatment. Finally, we will determine the role of ±-MSH in mitochondrial function in these immunoregulatory events. We expect that, in both cells types, ±-MSH treatment will induce an anti-inflammatory phenotype, dependent on mitochondrial immunometabolic stages.
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