Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats
Chunyan Wu, Su Hyeon Hwang, Yaoyao Jia, Joobong Choi, Yeon-Ji Kim, Dahee Choi, Duleepa Pathiraja, In-Geol Choi, Seung-Hoi Koo, Sung-Joon Lee
Chunyan Wu, Su Hyeon Hwang, Yaoyao Jia, Joobong Choi, Yeon-Ji Kim, Dahee Choi, Duleepa Pathiraja, In-Geol Choi, Seung-Hoi Koo, Sung-Joon Lee
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Brief Report Metabolism

Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats

Abstract

Olfactory receptors (ORs) are present in tissues outside the olfactory system; however, the function of these receptors remains relatively unknown. Here, we determined that olfactory receptor 544 (Olfr544) is highly expressed in the liver and adipose tissue of mice and regulates cellular energy metabolism and obesity. Azelaic acid (AzA), an Olfr544 ligand, specifically induced PKA-dependent lipolysis in adipocytes and promoted fatty acid oxidation (FAO) and ketogenesis in liver, thus shifting the fuel preference to fats. After 6 weeks of administration, mice fed a high-fat diet (HFD) exhibited a marked reduction in adiposity. AzA treatment induced expression of PPAR-α and genes required for FAO in the liver and induced the expression of PPAR-γ coactivator 1-α (Ppargc1a) and uncoupling protein-1 (Ucp1) genes in brown adipose tissue (BAT). Moreover, treatment with AzA increased insulin sensitivity and ketone body levels. This led to a reduction in the respiratory quotient and an increase in the FAO rate, as indicated by indirect calorimetry. AzA treatment had similar antiobesogenic effects in HFD-fed ob/ob mice. Importantly, AzA-associated metabolic changes were completely abrogated in HFD-fed Olfr544–/– mice. To our knowledge, this is the first report to show that Olfr544 orchestrates the metabolic interplay between the liver and adipose tissue, mobilizing stored fats from adipose tissue and shifting the fuel preference to fats in the liver and BAT.

Authors

Chunyan Wu, Su Hyeon Hwang, Yaoyao Jia, Joobong Choi, Yeon-Ji Kim, Dahee Choi, Duleepa Pathiraja, In-Geol Choi, Seung-Hoi Koo, Sung-Joon Lee

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Figure 2

AzA administration reduces adiposity and improves insulin sensitivity in HFD-fed WT mice but not HFD-fed Olfr544–/– mice.

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AzA administration reduces adiposity and improves insulin sensitivity in...
(A) Lipolysis in WT and Olfr544–/– (KO) mice (n = 4). (B) Body weight and (C) adipocyte tissue mass assessed by micro-CT in HFD-fed WT (n = 7–8) and Olfr544–/– (n = 4–5) mice after 6 weeks of treatment with AzA (50 mg/kg of body weight/day). Adipose tissue appears dark gray. (D) Oral glucose tolerance test (OGTT) in HFD-fed mice at 5 weeks after overnight fasting and (E) insulin tolerance test (ITT) in HFD-fed mice at 5.5 weeks after a 4-hour fast (n = 7–8 for WT mice and n = 5 for Olfr544–/– mice). Data are presented as the mean ± SEM. The HFD used in this study was a rodent diet containing 60% of calories from fat. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by Student’s t test or 1-way ANOVA followed by Tukey’s HSD test for comparison of 2 or more groups.