Abstract
Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.
Highlights
Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress
Leptin is an adipocyte-derived hormone that has originally been described to suppress appetite through its action on proopiomelanocortin (POMC) and agouti-related peptide (AgRP)/ neuropeptide Y (NPY) neurons located in the arcuate nucleus of the hypothalamus[2,3]
We assessed ER stress marker expression in arcuate Pomc and Agrp neurons and found that the levels of Atf[4], Atf[6], Xbp[1], and Bip mRNAs were higher in these two neuronal populations in P10 ob/ob mice (Fig. 1d)
Summary
Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Because childhood obesity is associated with many lifethreatening risks, including type 2 diabetes, there is an important need to understand the factors and mechanisms involved in the development of these pathological conditions. The density of projections from ARH neurons to other hypothalamic sites involved in the control of food intake is severely disrupted in postnatal leptin-deficient ob/ob mice and remains diminished throughout life[7]. Previous studies have demonstrated that ER stress and UPR signaling pathway activation play important roles in the development of obesity-induced insulin resistance and type 2 diabetes[9]. We find that the mechanisms underlying the effects of ER stress on ob/ob mice involve autophagy
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