Regulation of obesity and insulin resistance by hypoxia-inducible factors

Abstract

In obesity, dysregulated metabolism and aberrant expansion of adipose tissue lead to the development of tissue hypoxia that plays an important role in contributing to obesity-associated metabolic disorders. Recent studies utilizing adipocyte-specific hypoxia-inducible factor-α (HIF-α) gain- or loss-of-function animal models highlight the pivotal involvement of hypoxic responses in the pathogenesis of obesity-associated inflammation and insulin resistance. HIF-1α, a master transcription factor of oxygen homeostasis, induces inflammation and insulin resistance in obesity, whereas its isoform, HIF-2α, exerts opposing functions in these obesity-associated metabolic phenotypes. In this review, recent evidence elucidating functional implications of adipocyte HIFs in obesity and, more importantly, how these regulate obesity-associated inflammation, fibrosis, and insulin resistance will be discussed. Further, we propose that modulation of HIF-1 could be a potential novel therapeutic strategy for antidiabetic treatment.

Keywords: hypoxia-inducible factor-1; inflammation; oxygen.

Figure 1

Oxygen-dependent regulation of HIF-1α. Notes: When ample oxygen is present, proline residues in the ODD of the HIF-1α subunit are hydroxylated by PHDs that require oxygen as a substrate. The hydroxylated HIF-1α subunit is then recognized and bound by VHL, which targets HIF-1α for polyubiquitination and proteasomal degradation. HIF-1α asparagine residue is hydroxylated by the FIH blocking HIF-1α association with coactivator p300, which in turn prevents full transcriptional activation of HIF-1. Under hypoxic conditions, enzymatic activity of PHDs and FIH is inhibited and HIF-1α subunits are stabilized and translocated to the nucleus, where with binding partner HIF-1β and coactivator p300, HIF-1 binds to the HREs in the promoter of target genes that are involved in the process of hypoxic adaptation and survival. Abbreviations: BNIP3, BCL2/adenovirus E1B 19kDa protein-interacting protein 3; CA IX, carbonic anhydrase IX; EPO, erythropoietin; FIH, factor-inhibiting HIF; Glut, glucose transporter; HIF, hypoxia-inducible factor; HK, hexokinase; HREs, hypoxia-response elements; LDHA, lactate dehydrogenase A; ODD, oxygen-dependent domain; PHDs, prolyl hydroxylases; SCF, Skp1–Cul1–F-box-protein; VEGF, vascular endothelial growth factor; Ub, ubiquitin; VHL, von Hippel–Lindau tumor suppressor protein.

Figure 2

HIF-1α expression in obese adipose tissues. Notes: (A) Hematoxylin and eosin staining of adipose tissues of obese mice fed a high-fat diet for 15 weeks shows enlarged adipocytes with significant inflammatory cell infiltration (*). (B) HIF-1α is detected by immunohistochemistry (black arrows) in obese adipose tissues. Abbreviation: HIF, hypoxia-inducible factor.

Figure 3

Regulation of obesity and diabetes by HIFs. Notes: In obesity, insufficient blood perfusion and elevated oxygen consumption result in adipose tissues hypoxia that leads to induction of HIFs. HIF-1α contributes to the development of insulin resistance and other metabolic disorders by promoting obesity-associated inflammation and fibrosis. In contrast, HIF-2α exhibits protective roles against HIF-1α-mediated diabetic phenotypes. The pharmacological modulation of HIF activities can be an effective therapeutic strategy for antiobesity and diabetes therapies. Abbreviation: HIF, hypoxia-inducible factor.