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  • br Conflict of interest br Acknowledgments We thank Professo

    2022-08-09


    Conflict of interest
    Acknowledgments We thank Professor Chen Rui (Southeast University, China) for providing plasmid P1P2N-HIF1. This study was supported by research grants from National Natural Science Foundation of China (81573189, 81730087).
    Introduction The consumption of large amounts of dietary fats, particularly saturated fatty acids (SFAs), can impair hypothalamic neuronal circuitries that control whole-body pd0332991 homeostasis, leading to obesity (De Souza et al., 2005, Dziedzic et al., 2007, Horvath et al., 2010, Moraes et al., 2009, van de Sande-Lee and Velloso, 2012). At least part of this hypothalamic dysfunction emerges as a consequence of an inflammatory response that is triggered as early as one day after the introduction of a high-fat diet (HFD) and thus precedes systemic inflammatory activity, which is a hallmark of the obese phenotype (De Souza et al., 2005, Morari et al., 2014, Souza et al., 2016, Thaler et al., 2012, Valdearcos et al., 2017, Zhang et al., 2008). Increased pro-inflammatory activity is responsible for hypothalamic resistance to leptin and insulin, leading to the impairment of neuronal pathways that control energy homeostasis (Purkayastha et al., 2011, Zhang et al., 2008) and, in later stages, can induce neuronal apoptosis (Guyenet et al., 2013, Li et al., 2012, Moraes et al., 2009). Studies have shown that the anorexigenic POMC neuronal subpopulation of the hypothalamic arcuate nucleus (ARC) is the main target of late-stage diet-induced hypothalamic neuronal apoptosis, which may generate an imbalance in orexigenic/anorexigenic responses, favoring the progression of obesity (Horvath et al., 2010, Souza et al., 2016, Torri et al., 2002). Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that activates several genes in response to hypoxia or other potentially harmful conditions (Semenza, 2012). In the hypothalamus, HIF was shown to control the expression of POMC, impacting on whole body energy homeostasis (Varela et al., 2017, Zhang et al., 2011). The HIF-1 complex is a heterodimer composed of the α and β subunits. The protein levels of the α subunit are regulated by external stimuli, such as hypoxia and inflammation, while the β subunit, also called aryl hydrocarbon receptor nuclear translocator (ARNT), is constitutively present. In addition to its importance in the response to harmful conditions, the HIF-1 complex is also involved in the regulation of glucose and energy homeostasis by acting in β-cells, liver, muscle, adipose tissue, and the hypothalamus (Semenza, 2011, Zhang et al., 2010a), thus contributing to the development of obesity and type 2 diabetes (T2D) (Girgis et al., 2012, Rahtu-Korpela et al., 2014, Zhang et al., 2010b). Particularly, in the hypothalamus, HIF can be regulated by systemic glucose levels and in turn control POMC expression, which is an important component of the neuronal network that modulates whole-body glucose homeostasis (Varela et al., 2017, Zhang et al., 2011).
    Material and methods
    Results
    Discussion Energy homeostasis is a fundamental physiological process, which is mostly controlled by the hypothalamus (Dietrich and Horvath, 2013). This process relies on a complex regulatory system, which coordinately senses and responds to a number of signals that reflect the metabolic dynamics of the organism (Jeong et al., 2014, Ruud et al., 2017). In DIO, whole-body energy homeostasis is severely disturbed, resulting in positive energy balance (Velloso and Schwartz, 2011). This is due, at least in part, to an abnormal function of hypothalamic neurons that are affected by an inflammatory process occurring in the hypothalamus, which is induced by dietary fats (De Souza et al., 2005, Moraes et al., 2009, Thaler et al., 2012, Valdearcos et al., 2017, Valdearcos et al., 2014). Hypothalamic POMC neurons are critical for the correct sensing and modulation of a number of functions directly involved in whole-body energy homeostasis, such as food intake, thermogenesis, and glucose homeostasis (Ruud et al., 2017). Studies have shown that, in the course of DIO, POMC neurons are the subpopulation of hypothalamic neurons mostly affected by dietary fats (Gao et al., 2017, Moraes et al., 2009, Souza et al., 2016, Yi et al., 2017). However, whether inflammation has a direct and detrimental effect on hypothalamic POMC neurons is currently unclear. Therefore, elucidating the diverse mechanisms involved in HFD-induced hypothalamic neuronal dysfunction may contribute to the complete understanding of the pathophysiology of obesity and potently lead to the identification of new targets for the prevention and treatment of obesity.