CoPP Improves Liver Damage Caused By High-fat Diet By Regulating SIRT1 & Leptin And Serotonnin Regulate The Body's Energy Metabolism And Blood Sugar Balance Through Trpc5 Ion Channels In Pomc Nerve Cells Of The Hypothalamus

The liver is a central metabolic organ that regulates several key aspects of lipid metabolism,including fatty acid oxidation,lipogenesis,and lipoprotein uptake and secretion.The aberrant accumulation of fatty acids in the liver contributes to the progression of diabetes and non-alcoholic fatty liver disease.Lipid accumulation in the liver is a major hallmark of Non-alcoholic fatty liver diseases(NAFLD),thus,the modulation of key transcription factors regulating hepatic lipid metabolism,such as SREBPlc has been proposed to have great potential for NAFLD treatment.SIRT1 plays a crucial role in the DNA damage response,carcinogenesis and regulation of lifespan,which are mediated by its NAD+-dependent deacetylase activity.However,the exact biological function of SIRT1 in the liver requires further elucidation.Heme oxygenase(HO)is the rate-limiting enzyme in the degradation of heme into carbon monoxide,biliverdin,and free iron.To date,three isoforms of heme oxygenase are known,including HO-1,HO-2,HO-3.HO-1 has been demonstrated to exert multiple biological effects,including anti-inflammatory,anti-apoptotic and anti-proliferative actions.Cobalt protoporphyrin(CoPP)is known to be a potent and effective inducer of HO-1 activity in many tissues.Previous studies indicate that HO-1-mediated increases in adiponectin can ameliorate the deleterious effects of obesity and metabolic syndrome associated with cardiovascular disease and diabetes.However,the effect of HO-1 on liver lipid metabolism has remained elusive.In this study,we report that CoPP protects against HFD-induced metabolic damage by decreasing SREBP-lc expression and improving antioxidant and anti-inflammatory status through a SIRT1-mediated mechanism.Our results suggest that the HO-1-mediated increase in SIRT1 plays a crucial role in improving liver metabolic profiles,including NAFLD and diabetes.Keeping energy balance and glucose homeostasis is a complex state that include multiple regulatory processes,of which manipulating foraging and food-seeking behaviors plays a predominant role.Leptin and/or serotonin-induced activation of hypothalamic POMC exerts anorexigenic effects,which could be potentially used to therapy obesity and diaebets.In contrast,activation of neighbouring NPY/AgRP results in an hypophagia phenotype.The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear.Here,we show that neuronal and pro-opiomelanocortin(Pomc)-specific loss of tran-sient receptor potential cation 5(TrpC5)subunits is sufficient to decrease energy expenditure and in-crease food intake resulting in elevated body weight.Deficiency of TrpC5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor(Ht2Cr)agonists.The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons.We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons.Together,our results link TrpC5 subunits in the brain with leptin-and serotonin 2C receptor-dependent changes in neuronal activity,as well as energy balance,feeding behavior,and glucose metabolism.