Abstract
The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.
Highlights
Leptin, predominantly produced by and secreted from white adipocytes, conveys information 3 regarding the status of energy storage and availability to the brain, to maintain energy homeostasis. 4 It binds the leptin receptor in hypothalamic neurons to reduce food intake and increase energy 5 expenditure in coordination with other adipokines and gastric peptides (Allison & Myers, 2014; 6 Pan & Myers, 2018)
Summary: Here we describe a novel molecular aspect by which the hepatic endocannabinoid/CB1R system contributes to hepatic leptin resistance by regulating soluble leptin receptor levels via C/EBP homologous protein (CHOP). Running Title: CB1 Regulates soluble isoform of leptin receptor (sOb-R) levels via CHOP
Its reduced levels in diet-induced obesity (DIO) contributes to 4 hyperleptinemia and leptin resistance, effects that are known to be regulated by the 5 endocannabinoid/CB1R system
Summary
Predominantly produced by and secreted from white adipocytes, conveys information 3 regarding the status of energy storage and availability to the brain, to maintain energy homeostasis. 4 It binds the leptin receptor in hypothalamic neurons to reduce food intake and increase energy 5 expenditure in coordination with other adipokines and gastric peptides (Allison & Myers, 2014; 6 Pan & Myers, 2018). 4 It binds the leptin receptor in hypothalamic neurons to reduce food intake and increase energy 5 expenditure in coordination with other adipokines and gastric peptides (Allison & Myers, 2014; 6 Pan & Myers, 2018). Leptin stimulates the secretion of α-melanocortin stimulating 7 hormone (α-MSH) from proopiomelanocortin (POMC) neurons at the arcuate nucleus (ARC), and 8 inhibits the secretion of the orexigenic peptides neuropeptide-Y (NPY) and Agouti-related protein 9 (AgRP) (Flak & Myers, 2016). Genetic leptin deficiency or lack of functional leptin receptor results in morbid obese and insulin resistance phenotypes in animals (ob/ob or db/db mice, respectively) Congenital leptin deficiencies are rare, leading to hyperphagia and early-onset obesity, which can be reversed with a leptin replacement therapy (Mantzoros, 1999). Most cases of obesity are characterized by hyperleptinemia, indicating that obesity is a leptin-resistant state, where leptin signaling is impaired
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