Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation

Abstract

Objective Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. Methods Ormdl3 -deficient ( Ormdl3 −/− ) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3 −/− mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. Results BAT thermogenesis and WAT browning were significantly impaired in Ormdl3 −/− mice upon cold exposure or administration with the β3 adrenergic agonist. In addition, compared to WT mice, Ormdl3 −/− mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3 −/− mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3 −/− mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. Conclusion Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance.

Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions

“…For instance, sphingolipid levels were found to be unchanged in transgenic Ormdl3 overexpression and whole-body Ormdl3 KO mice, and this observation was recapitulated in HEK cells (17). However, many studies report some effect of Ormdl3 overexpression or deletion on systemic sphingolipid levels with minor changes to rodent health measures (14, 18, 19). For example, while absence of Ormdl3 has been associated with increased levels of sphingolipids within the brain, Ormdl3 knockout mice appeared metabolically healthy and similar to control mice (19).…”

“…ORMDL3 has been implicated in a variety of disorders including asthma, inflammatory bowel disease, and obesity (8,(11)(12)(13). Recently, it was reported that mice with a whole-body knockout of Ormdl3 when challenged with cold exposure or HFD exhibit impaired regulation of brown adipose tissue thermogenesis, white adipose tissue browning, and insulin resistance (14). Yet the contribution of β-cells to the systemic glucose homeostasis remained unknown.…”

Contribution of specific ceramides to obesity-associated metabolic diseases

“…In genome-wide association studies, the SPT suppressor ORMDL3 was identified as an obesity-related gene, and its expression in human subcutaneous WAT inversely correlates with BMI [ 235 , 236 ]. Conversely, Ormdl3 -deficient mice show elevated ceramide levels in WAT, increased body weight gain upon high-fat diet feeding, and insulin resistance, which was attributed to decreased thermogenesis and impaired WAT browning [ 235 ].…”

“…In genome-wide association studies, the SPT suppressor ORMDL3 was identified as an obesity-related gene, and its expression in human subcutaneous WAT inversely correlates with BMI [ 235 , 236 ]. Conversely, Ormdl3 -deficient mice show elevated ceramide levels in WAT, increased body weight gain upon high-fat diet feeding, and insulin resistance, which was attributed to decreased thermogenesis and impaired WAT browning [ 235 ]. Myriocin treatment reversed the detrimental phenotypes in these mice, indicating that the inhibition of ceramide synthesis by ORMDL3 is a critical mechanism for maintaining adipose tissue function and systemic energy homeostasis [ 235 ].…”

“…Conversely, Ormdl3 -deficient mice show elevated ceramide levels in WAT, increased body weight gain upon high-fat diet feeding, and insulin resistance, which was attributed to decreased thermogenesis and impaired WAT browning [ 235 ]. Myriocin treatment reversed the detrimental phenotypes in these mice, indicating that the inhibition of ceramide synthesis by ORMDL3 is a critical mechanism for maintaining adipose tissue function and systemic energy homeostasis [ 235 ]. Furthermore, by adipocyte-specific deletion of Sptlc2 in obese mice, Chaurasia and colleagues found that the inhibition of ceramide synthesis decreased C 24:0 and C 24:1 ceramides in epididymal- and C 16:0 –C 24:0 and C 24:1 ceramides in subcutaneous WAT, which improved adipose tissue function preferentially in subcutaneous depots [ 23 ].…”