Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity

Author(s)

Gaspar, Joana M. ^[1] ; Mendes, Natalia Ferreira ^{[2, 1]} ; Correa-da-Silva, Felipe ^[1] ; de Lima-Junior, Jose C. ^[1] ; Gaspar, Rodrigo C. ^[3] ; Ropelle, Eduardo R. ^[3] ; Araujo, Eliana P. ^{[2, 1]} ; Carvalho, Humberto M. ^[4] ; Velloso, Lido A. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Lab Cell Signaling, Obes & Comorbid Res Ctr, Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Fac Nursing, Campinas, SP - Brazil

^[3] Univ Campinas UNICAMP, Lab Mol Biol Exercise, Limeira, SP - Brazil

^[4] Univ Fed Santa Catarina, Dept Phys Educ, Florianopolis, SC - Brazil

• Document type: Journal article
• Source: BRAIN BEHAVIOR AND IMMUNITY; v. 73, p. 550-561, OCT 2018.
• Web of Science Citations: 1

Abstract

Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO). We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days. The expression of HIF-1alpha and HIF-1beta was measured by PCR and western blotting and its hypothalamic distribution was evaluated by fluorescence microscopy. Inhibition of HIF-1beta in arcuate nucleus of hypothalamus was performed using stereotaxic injection of shRNA lentiviral particles and animals were grouped under normal chow diet or high fat diet for 14 days. Using bioinformatics, we show that in humans, the levels of HIF-1 transcripts are directly correlated with those of hypothalamic transcripts for proteins involved in inflammation, regulation of apoptosis, autophagy, and the ubiquitin/proteasome system; furthermore, in rodents, hypothalamic HIF-1 expression is directly correlated with the phenotype of increased energy expenditure. In mice, DIO was accompanied by increased HIF-1 expression. The inhibition of hypothalamic HIF-1 by injection of an shRNA resulted in a further increase in body mass, a decreased basal metabolic rate, increased hypothalamic inflammation, and glucose intolerance. Thus, hypothalamic HIF-1 is increased during DIO, and its inhibition worsens the obesity-associated metabolic phenotype. Thus, hypothalamic HIF-1 emerges as a target for therapeutic intervention against obesity. (AU)

• FAPESP's process: 15/10078-2 - Effect of a high caloric diet in the expression of Hypoxia- inducible factor-1 (HIF1): Role in obesity through deregulation of pomc gene
• Grantee: Joana Margarida Navalho Gaspar
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/17810-3 - Evaluation of TGF-b1 function in the hypothalamus of animals with obesity and diabetes induced by high-fat diet
• Grantee: Natália Ferreira Mendes
• Support Opportunities: Scholarships in Brazil - Doctorate