Olfactomedin 2 deficiency protects against diet-induced obesity

Abstract

Background and aims: Olfactomedin 2 (OLFM2; also known as noelin 2) is a pleiotropic protein that plays a major role in olfaction and Olfm2 null mice exhibit reduced olfactory sensitivity, as well as abnormal motor coordination and anxiety-related behavior. Here, we investigated the possible metabolic role of OLFM2.

Methods: Olfm2 null mice were metabolically phenotyped. Virogenetic modulation of central OLFM2 was also performed.

Results: Our data showed that, the global lack of OLFM2 in mice promoted anorexia and increased energy expenditure due to elevated brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). This phenotype led to resistance to high fat diet (HFD)-induced obesity. Notably, virogenetic overexpression of Olfm2 in the lateral hypothalamic area (LHA) induced weight gain associated with decreased BAT thermogenesis.

Conclusion: Overall, this evidence first identifies central OLFM2 as a new molecular actor in the regulation of whole-body energy homeostasis.

Keywords: Brown adipose tissue; Browning; Lateral hypothalamic area; Obesity; Olfactomedin 2; Thermogenesis.

Fig. 1.

Effect of global OLFM2 deficiency on energy balance in high fat diet fed mice. (A) Body weight change after HFD exposure, (B) food intake, (C) body composition, (D) fat pads weight, (E) leptin serum levels, (F) energy expenditure (EE), (G) respiratory quotient (RQ), (H) body temperature, (I) representative thermal images, (J) temperature of the BAT area, (K) western blot representative images, (L) BAT UCP1 protein levels, (M) BAT mRNA levels of thermogenic/oxidative markers and (N) BAT neurotransmitter levels of WT and OLFM2 KO mice fed a HFD. Data are expressed as MEAN ± SEM. N = 6 mice/group in all the panels, except for body composition data (C) where N = 5 mice/group. Statistical significance was determined by Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT HFD. In panel B: i) the asterisk (*P < 0.05) above the horizontal middle line indicates the statistical difference WT HFD vs. OLFM2 KO HFD mice in total food intake (light phase + dark phase); ii) the asterisk (*P < 0.05) above the OLFM2 KO HFD white bar indicate the statistical difference WT HFD vs. OLFM2 KO HFD mice in the light phase food intake; iii) the P = 0.07 above the OLFM2 KO HFD grey bar indicates the P value between WT HFD vs. OLFM2 KO HFD mice in the dark phase food intake.

Fig. 2.

Effect of Olfm2 overexpression within the lateral hypothalamic area on energy balance in standard diet fed mice. (A) Representative confocal micrographs depicting Olfm2 mRNA (magenta) and DAPI (blue) fluorescence in the brain coronal section of a WT mice. Scale bar = 1000 μm, (B) Olfm2 mRNA levels in the LHA (N = 8–11 mice/group), (C) body weight change, (D) daily food intake (N = 11 mice/group), (E) average food intake (N = 11 mice/group), (F) representative thermal images and (G) temperature of the BAT area (N = 8–11 mice/group) after stereotaxic administration of AAVs encoding GFP or OLFM2 in the LHA of mice fed a SD. Data are expressed as MEAN ± SEM. Statistical significance was determined by Student’s t-test. *P < 0.05, **P < 0.01 vs. GFP.