OR30-2 Brain NPR-B deficiency attenuates high-fat diet-induced hepatic steatosis in mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR30-Central Regulation of Appetite & Feeding
Basic/Translational
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 304 (Moscone Center)
Yui Yamashita*1, Nobuko Yamada-Goto1, Goro Katsuura1, Yukari Ochi1, Yuri Miyazaki2, Itaru Imayoshi3, Hiroyuki Ariyasu1, Naotetsu Kanamoto1, Masako Miura1, Akihiro Yasoda1, Hiroshi Arai1, Kousaku Ohinata2, Ryoichiro Kageyama3 and Kazuwa Nakao1
1Kyoto University Graduate School of Medicine, Kyoto, Japan, 2Kyoto University Graduate School of Agriculture, Kyoto, Japan, 3Institute for Virus Research Kyoto University, Kyoto, Japan
[Background and objectives] C-type natriuretic peptide (CNP) and its receptor, NPR-B (also known as guanylyl cyclase B), are abundantly distributed in the hypothalamus which is the integrative control center for energy regulation. We previously reported that intracerebroventricularly administered CNP significantly suppressed fasting-induced refeeding and nocturnal food intake in mice. Furthermore, guanylyl cyclase and its downstream cGMP signaling are essential regulators of feeding in invertebrates. Therefore, we hypothesized that CNP/NPR-B signaling in the brain could be a new regulator of food intake and energy expenditure. To test this hypothesis, we generated brain-specific NPR-B deficient mice (NPR-B deficient mice), and explored the role of central CNP/NPR-B signaling in energy regulation.

[Animals and methods] To generate brain-specific NPR-B deficient mice, we crossed mutant mice carrying the floxed NPR-B gene with transgenic mice expressing Cre recombinase under the control of the rat nestin promoter. In this study, 8-week-old male mice were given free access to water and either standard diet (SD) (F-2; 12 % calories from fat) or high-fat diet (HFD) (D12492; 60 % calories from fat). At 16 weeks of age, the animals were sacrificed for further analysis.

[Results] There was no difference in naso-anal length, food intake, or oxygen consumption between NPR-B deficient mice and control mice on either a SD or a HFD. Body weight of NPR-B deficient mice fed a SD was significantly lower than control mice from 11 weeks of age. When fed a HFD, brain NPR-B deficient mice were resistant to weight gain. At 16 weeks of age, NPR-B deficient mice fed a HFD were 13% less in body weight than control mice. And, the weight of the liver and the mesenteric adipose tissue were significantly decreased in NPR-B deficient mice fed a HFD compared with control mice. In addition, NPR-B deficient mice fed a HFD exhibited significantly decreased hepatic triglyceride and cholesterol contents, and fatty acid translocase (also known as CD36) mRNA expression in the liver compared with control mice. These changes were accompanied by significantly decreased plasma insulin and FFA levels in NPR-B deficient mice fed a HFD compared with control mice. In the mesenteric adipose tissue, the expression of UCP2 mRNA was significantly decreased in NPR-B deficient mice fed a HFD compared with control mice. Furthermore, in the hypothalamus, NPR-B deficient mice fed a HFD showed significantly increased POMC mRNA and CART mRNA expression compared with control mice.

[Conclusions] In this study, we demonstrated that brain NPR-B deficiency prevented high-fat diet-induced fat accumulation in the liver and the visceral adipose tissue, which might be accompanied by improvement of systemic insulin sensitivity. Our findings suggest that CNP/NPR-B signaling in the brain could be a new central factor that regulate peripheral lipid metabolism.

Nothing to Disclose: YY, NY, GK, YO, YM, II, HA, NK, MM, AY, HA, KO, RK, KN

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm