Abstract
The earliest hypoxia-inducible factor (HIF) function was to respond to hypoxia or hypoxic conditions as a transcription factor. Recent studies have expanded our understanding of HIF, and a large amount of evidence indicates that HIF has an essential effect on central regulation of metabolism. The central nervous system’s response to glucose, inflammation, and hormones’ main influence on systemic metabolism are all regulated by HIF to varying degrees. In the hypothalamus, HIF mostly plays a role in inhibiting energy uptake and promoting energy expenditure, which depends not only on the single effect of HIF or a single part of the hypothalamus. In this paper, we summarize the recent progress in the central regulation of metabolism, describe in detail the role of HIF in various functions of the hypothalamus and related molecular mechanisms, and reveal that HIF is deeply involved in hypothalamic-mediated metabolic regulation.
Highlights
The central nervous system (CNS) receives many peripheral signals, including nutrient signals, hormone and gastric vagal afferent signals transmit and integrate peripheral energy information through a complex neural network, regulating peripheral target organs such as adipose tissue, through the nerve-body fluid pathway
MTOR can be considered as an important part of energy homeostasis regulated by CNS because it is a downstream target of phosphatidylinositol 3-kinase (PI3K) pathway stimulated by insulin and has the function of regulating glucose/lipid homeostasis, body weight and energy consumption through hypothalamus [66]
Considering that Unfolded protein response (UPR) may promote hypoxia-inducible factor (HIF) through inositol-requiring enzyme 1a (IRE1a)-X box-binding protein 1 (XBP1) [69, 70], while IKK/ NF-kB and endoplasmic reticulum (ER) stress promote each other and induce energy imbalance leading to obesity during high-fat diet (HFD) feeding [68], it can be inferred that HIF can act as downstream negative feedback to inhibit NF-kB in the process of ER stress, so as to reduce the adverse effects of this stress
Summary
The central nervous system (CNS) receives many peripheral signals, including nutrient signals, hormone and gastric vagal afferent signals transmit and integrate peripheral energy information through a complex neural network, regulating peripheral target organs such as adipose tissue, through the nerve-body fluid pathway. Glucose, lipids and other common nutrients have a similar mechanism to induce mitochondrial ROS production in the hypothalamus alongside with an activity raise in mitochondrial respiration, so the central nervous system, after receiving lipid and glucose signals, can cause certain systemic metabolic regulation measures by upregulated ROS.
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