Hypoxia Inducible Factor as a Central Regulator of Metabolism - Implications for the Development of Obesity

Abstract

The hypothalamus plays a major role in the regulation of food intake and energy expenditure. In the last decade, it was demonstrated that consumption of high-fat diets triggers the activation of an inflammatory process in the hypothalamus, inducing neurofunctional alterations and contributing to the development of obesity. Hypoxia-inducible factors (HIFs) are key molecules that regulate cellular responses to inflammation and hypoxia, being essential for the normal cell function and survival. Currently, evidence points to a role of HIF pathway in metabolic regulation that could also be involved in the progression of obesity and metabolic diseases. The challenge is to understand how HIF modulation impacts body mass gain and metabolic disorders such as insulin resistance. Distinct animal models with tissue-specific knocking-out or overexpression of hypoxia signaling pathway genes revealed a cell-specificity in the activation of HIF pathways, and some of them have opposite phenotypes among the various HIFs gain- and loss-of-function mouse models. In this review, we discuss the major findings that provide support for a role of HIF pathway involvement in the regulation of metabolism, especially in glucose and energy homeostasis.

Keywords: HIF complex; energy homeostasis; hypothalamus; inflammation; metabolic disorders; obesity.

FIGURE 1

Hypothalamic regulation of energy homeostasis: the hypothalamus senses and integrates peripheral adipostatic hormones that circulate in levels proportionate to nutritional status and adipose tissue stores. Under fasting conditions ghrelin, secreted by the stomach, binds to its receptor in AgRP neurons in the ARC, leading to its activation. AgRP neuronal activation increased the release of AgRP that is an antagonist of MC4R in the PVN neurons; at the same time, AgRP neurons also release of GABA neurotransmitter that inhibited POMC neurons, and consequently increasing appetite and decreased energy expenditures. In the fed state, insulin and leptin act directly on their receptors, both in POMC and AgRP neurons in the ARC of the hypothalamus to control energy homeostasis; insulin and leptin induce inhibition of AgRP and activation of POMC neurons. POMC neuronal activation involves the processing of POMC with formation of α-MSH that is an agonist of MC4R and consequently activating PVN neurons. PVN activation culminates in satiety (decreased food intake) and stimulation of energy expenditure. AgRP, agouti related protein; MC4R, melanocortin 4 receptor; GABA, gamma-aminobutyric acid; POMC, proopiomelanocortin; α-MSH, alpha-melanocyte-stimulating hormone; PVN, paraventricular nucleus.

FIGURE 2

Hypoxia-inducible factor-1 regulation. Under normoxia, HIF-1α is hydroxylated on proline residues 402 and 564 by prolyl hydroxylases (PHD). This hydroxylation is a target for von Hippel-Lindau protein (VHL) binding, a E3 ligase that targets HIF-1α for ubiquitination and proteasomal degradation. Factor inhibiting HIF-1 (FIH-1) hydroxylated an asparagine residue (803) that blocks the binding of the coactivator p300/CBP (A). Under hypoxia, PDH and FIH are inhibited and HIF-1α is stabilized to dimerize with HIF-1β, and binds to target genes at the DNA, recruits p300, and activates transcription of several genes involved in immunity, angiogenesis, metabolism, survival, and proliferation. Immune and inflammatory stimuli can also regulate the HIF pathway, primarily via activation of Toll-like receptors (TRL) and NF-kB activation. NF-Kb is translocated to the nucleus where it regulates the expression of HIF- α mRNA (B). CBP/p300, Creb Binding Protein/p300; LPS, lipopolysaccharide; PHD, prolyl hydroxylases; VHL, von Hippel-Lindau protein; FIH-1, factor inhibiting HIF-1; P-OH, hydroxylation in proline residues; N-OH, hydroxylation in asparaginyl residues; TLR-4, Toll-like receptors; ub, ubiquitin; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells.

FIGURE 3

Hypoxia-inducible factor-1 regulation of food intake. HIF in POMC neurons can function as a glucose sensor. After a meal, the increase in neuronal concentration activates neuronal glycolysis producing pyruvate, lactate, and intermediaries from the tricarboxylic acid (TCA) cycle. These metabolites inhibit PHD and FIH enzymes leading to the HIF stabilization. Conversely, these metabolites also block AMPK activation that regulates and increase the expression of HIF-α mRNA. Increase in HIF induces its translocation to the nucleus to bind POMC promoter and consequently stimulating the transactivation of POMC (A). Obesity and consumption of high-fat diet induces an inflammatory condition in the hypothalamus, mostly driven by microglia and glial cells. Our main hypothesis is that inflammation in hypothalamic glial cells (increased TGF-β, TLR4 signaling, and increased NO production) leads to a stabilization of HIF that consequently transactivates several genes involved in the regulation of metabolism and inflammatory process as a compensatory mechanism for the nutritional excess (B). CBP/p300, Creb Binding Protein/p300; PHD, prolyl hydroxylases; FIH-1, factor inhibiting HIF-1; AMPK, 5’ AMP-activated protein kinase; POMC, proopiomelanocortin.