Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance

Abstract

ObjectiveAdipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis.MethodWhite and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process.ResultsHig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes.ConclusionsWe conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.

Stress-responsive HILPDA is necessary for thermoregulation during fasting

“…These may, for example, include compensations such as change in body posture and blood flow or changes in skeletal muscle thermogenesis through uncoupling of the SERCA pump by Sarcolipin (Rowland, et al 2015). It is also possible that, in our genetic background, BAT function below thermoneutrality is altered when Hilpda is absent, similar to what has been seen in the adipose tissue-specific KO model (Dijk et al 2017; DiStefano et al 2016) In agreement with recently published reports, we did not find a cell-autonomous defect of HILPDA KO adipocytes in their differentiation capacity or lipolysis (Dijk et al 2017; DiStefano et al 2016). Hilpda was, however, required for body temperature defense after fasting, and the hypothermia of the KO mice was associated with rebound hyperphagia.…”

“…It is now evident that additional stresses and transcription factors, such as PPARs, cAMP and nutrient imbalance induce Hilpda expression (this work) and (Dijk et al 2017; DiStefano et al 2015; DiStefano et al 2016; Gimm et al 2010; Mattijssen et al 2014; Wang, et al 2010). The mechanistic details of Hilpda-dependent lipid accumulation are not known yet and require additional biochemical investigation.…”

“…Previous reports have shown that Hilpda is expressed in human and murine adipocytes and responds to PPAR- and b-adrenergic signaling (Dijk et al 2017; DiStefano et al 2016). To determine the regulation of Hilpda expression and its impact on adipocyte differentiation in our genetically engineered model we isolated the stromal vascular fraction (SVF) from interscapular BAT and differentiated it in vitro (Fig.…”

“…Liver- and adipose-specific Hilpda deletion has been reported to improve glucose tolerance (DiStefano et al 2015; DiStefano et al 2016). The glucose tolerance test after 16h of overnight fasting in our whole-body KO model showed a trend towards higher glucose peak levels in the absence of Hilpda but it did not reach statistical significance (Fig.…”

“…Genetic manipulation in murine liver has implicated HILPDA in triglyceride accumulation by mechanisms involving PPARα-dependent Hilpda induction, triglyceride secretion and regulation of lipolysis, although direct inhibition of lipase activity was not found (DiStefano, et al 2015; Mattijssen, et al 2014). Additionally, deletion of Hilpda in WAT and/or BAT did not impact lipolysis, despite its robust induction during adipocyte differentiation in vitro and nutritional manipulations in vivo (Dijk, et al 2017; DiStefano, et al 2016). …”