Stress-responsive HILPDA is necessary for thermoregulation during fasting

Hypoxia-Inducible Lipid-Droplet Associated protein (HILPDA) has been shown to localize to lipid droplets in nutrient responsive cell types such as hepatocytes and adipocytes. However, its role in the control of whole-body homeostasis is not known. We sought to measure cell-intrinsic and systemic stress responses in a mouse strain harboring whole body Hilpda deficiency. We generated a genetically engineered mouse model of whole body HILPDA deficiency by replacing the coding HILPDA exon with Luciferase. We subjected the knockout animals to environmental stresses and measured whole-animal metabolic and behavioral parameters. Brown adipocyte precursors were isolated and differentiated in vitro to quantify the impact of HILPDA ablation in lipid storage and mobilization in these cells. HILPDA knockout animals are viable and fertile, but show reduced ambulatory activity and oxygen consumption at regular housing conditions. Acclimatization at thermoneutral conditions abolished the phenotypic differences observed at 22°C. When fasted, HILPDA KO mice are unable to maintain body temperature and become hypothermic at 22°C, without apparent abnormalities in blood chemistry parameters or tissue triglyceride content. HILPDA expression was upregulated during adipocyte differentiation and activation in vitro, however, it was not required for lipid droplet formation in brown adipocytes. We conclude that HILPDA is necessary for efficient fuel utilization suggesting a homeostatic role for Hilpda in sub-optimal environments.

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