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    • Another important outcome of reducing hypothalamic HIF in

    2021-11-30

    Another important outcome of reducing hypothalamic HIF in DIO was the increase in gliosis and hypothalamic inflammation. Both experimental and human studies have shown that hypothalamic inflammation plays an important role in obesity by inducing resistance to anorexigenic signals, such as insulin and leptin (De Souza et al., 2005, Kleinridders et al., 2009, Li et al., 2012, Milanski et al., 2009, Morari et al., 2014, Thaler et al., 2012, Valdearcos et al., 2014, van de Sande-Lee and Velloso, 2012, Zhang et al., 2008). Also, in a hypercaloric environment the persistent elevation of microglial reactivity and consequent TNF-α secretion induces mitochondrial stress in POMC neurons(Yi et al., 2017), which can result in POMC neuron apoptosis (Moraes et al., 2009, Thaler et al., 2012). Pharmacological and genetic approaches used to dampen the inflammation mediated by each of these mechanisms have produced encouraging results with respect to the control of body adiposity and whole-body metabolism (Valdearcos et al., 2017). Our results show that AgRP neurons do not express HIF-1 complex, however, the downregulation of HIF-1β in the arcuate nucleus in induces a significant increase in AgRP expression. We also observed a significant increase in inflammatory markers (for instance IL-1β, TNF-α, TLR-4). Scarlett and colleagues in 2008 have demonstrated that IL-1β activates AgRP mRNA-expressing neurons in the ARC (Scarlett et al., 2008). The treatment of neuronal cell line (N38) with saturated fatty Melphalan (stearic acid) stimulates AgRP expression in a dose-dependent manner (Wang et al., 2016). The activation of TLR4-dependent inflammation pathway was involved in stearic acid – stimulated AgRP/NPY expression (Dalvi et al., 2017, Wang et al., 2016). We hypothesized that the potential mechanism to increase AgRP expression in mice fed a high-fat diet with downregulation of HIF-1β in the arcuate nucleus induces a significant increase in the inflammatory process mediated by the increase in TLR4 and IL-1β. A number of studies have shown that hypothalamic neuronal dysfunction occurring in obesity impacts on the regulation of whole-body energy expenditure, at least in part because of abnormal regulation of BAT thermogenic activity (Ruud et al., 2017). Here, we demonstrated that in DIO, downregulation of the HIF-1 complex in the ARC resulted in decreased thermogenesis associated with a decrease in UCP-1 levels and increased fat accumulation in BAT. Similar results for UCP-1 were observed in animals feeding on chow diet, suggesting that HIF-1 in arcuate nucleus can have an important function in the regulation of thermogenesis independently of diet. We also observed that whole-body energy expenditure was decreased, suggesting that the hypothalamic HIF-1 complex has important roles in the regulation of whole-body energy expenditure and in BAT thermogenesis under thermoneutral conditions. No previous studies have evaluated the impact of hypothalamic HIF-1 in the activity of BAT. However, studies have evaluated the direct role of HIF-1 in BAT; the HIF complex (isoform 2) in BAT is one of the factors that contribute to BAT adaptation to obesity (protective effect), regulating thermogenic responses through UCP-1 expression (Garcia-Martin et al., 2015, Vucetic et al., 2011). Obese mice deficient in adipocyte-specific HIF2 displayed BAT dysregulation associated with reduced levels of UCP1 and an impairment of the thermogenic response to cold exposure(Garcia-Martin et al., 2015). It has been recently demonstrated that constitutive HIF-1α activation in adipose tissue promotes weight gain associated with reduced brown adipose tissue function and oxygen consumption (Jun et al., 2017). Thus, HIF-1 can control BAT activity by both direct and indirect mechanisms. In the last part of the study, we showed that inhibition of hypothalamic HIF-1 resulted in a phenotype of glucose intolerance associated with an increase in serum insulin levels. In addition, both in DIO and chow diet, there were increases in serum and liver triglyceride levels, which resulted in hepatic steatosis. Our results points to an important role of hypothalamic HIF-1 complex in the regulation of lipid and glucose metabolism. It was previously known that HIF-1 and HIF-2 in the liver exerted important functions in the regulation of glucose and lipid metabolism (Arias-Loste et al., 2015, Ramakrishnan et al., 2016, Rankin et al., 2007, Wang et al., 2009). Particularly, liver-specific deletion of HIF-1β results in increased hepatic gluconeogenesis and lipogenic gene expression but reduced hepatic lipid storage (Wang et al., 2009). Also, mice with loss of VHL in hepatocytes had a severe HIF-dependent steatosis (Rankin et al., 2007). However, neuronal deletion of FIH, with a resulting increase in HIF activity, promotes a reduction in liver steatosis (Zhang et al., 2010a), further supporting a role for the brain HIF-1 complex in the regulation of liver metabolism.