Abstract
Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.
Highlights
Energy balance relies on a tightly regulated homeostatic system matching food intake with energy expenditure [1]
IF staining showed that inositol-requiring enzyme 1a (IRE1a) was colocalized with POMC-expressing neurons in the arcuate nucleus (ARC) of control mice, but this colocalization was largely absent in POMC neuron-specific IRE1a knockout (PIKO) mice
To explore the mechanisms underlying the lean phenotype of PIKO mice, we measured the protein levels of a-melanocyte-stimulating hormone (a-MSH), a key Previous works have shown that IRE1a plays an important role in endoplasmic reticulum (ER) stress [17], autophagy [15] and insulin secretion [33]
Summary
Energy balance relies on a tightly regulated homeostatic system matching food intake with energy expenditure [1]. The central nervous system (CNS), especially the hypothalamus, plays a key role in the regulation of energy homeostasis and insulin action [2]. Because obesity and type 2 diabetes (T2D) represent an increasing health risk worldwide [4], exploring the nature of this dysfunction is high priority. Epidemiological studies have shown a relationship between dietary fat intake and obesity; high-fat diet (HFD)-induced obesity has been used commonly for the study of the mechanisms underlying dietary-induced obesity and insulin resistance [5]. Neurons expressing pro-opiomelanocortin (POMC), defined as part of the melanocortin system, play an important role in regulating food intake and energy expenditure [6], which is considered a promising target for the treatment of obesity [7]
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