Endocrine Abstracts

Obesity, a complex metabolic disorder characterised by excessive adipose tissue accumulation, is associated with numerous health complications. This study aimed to investigate the molecular mechanisms underlying obesity, focusing on the role of hypoxia-inducible factor 1 alpha (HIF1α). Our findings establish a novel link between HIF1α and the pathogenesis of obesity-related conditions. We uncovered a connection between HIF1α and diabetic neuropathy, a prevalent obesity-associated complication. Our results demonstrate that HIF1α levels play a role in the development of neuropathic pain associated with diabetes. Utilising HIF1α knockout mice, we observed a substantial reduction in pain behaviours, with the mechanical withdrawal threshold significantly reduced by ~48% (***p, n=6) in DMOG-treated mice when compared to DMOG-treated HIF1αKO and vehicle-treated wild-type mice. highlighting the pivotal role of HIF1α in pain sensitivity modulation. Mice on a high-fat diet had ~50% (***p, n =6) reduced heat withdrawal latency and mechanical withdrawal threshold from week 3 onwards when compared to wild-type and HIF1αKO mice. Proteomics analysis identified 387 differentially expressed genes, including 259 upregulated and 128 downregulated genes, with STRING and DAVID analysis showing mitochondrial ATP production as a top affected function. SeaHorse analysis confirmed the reduced ATP production in hypoxia-modelled neurons compared to DMOG-treated HIF1α knockout controls. On average ATP production was 199.5 ± 35.5 pmol/min in treated HIF1α knockout compared to 107.7 ± 12.0 pmol/min (* P=0.04, n =5) in hypoxia-induced neurons, basal respiration was also decreased in hypoxia-induced neurons at 157.0 ± 20.4 pmol/min compared to 283.8 ± 48.7 pmol/min of DMOG-treated HIF1α knockout controls (* P=0.04, n =5). Targeting HIF1α emerges as a promising therapeutic approach for effectively managing obesity-associated disorders, encompassing diabetic neuropathy. The continual exploration of the intricate interplay between HIF1α and obesity-related pathologies holds vast potential for the development of future therapeutic strategies.