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Nutrient-Gene Interactions

Inhibition of Hedgehog Signaling Protects Adult Mice from Diet-Induced Weight Gain¹

Kimberly K. Buhman^*, Li Chun Wang, Yuzhu Tang^*, Elzbieta A. Swietlicki^*, Susan Kennedy^*, Yan Xie^*, Zhong-Yi Liu, Linda C. Burkly, Marc S. Levin^*,**, Deborah C. Rubin^* and Nicholas O. Davidson^*,,2

^* Departments of Internal Medicine, and Pharmacology and Molecular Biology, Washington University School of Medicine, St. Louis, MO 63110; ^** Specialty Care Service Line, St. Louis VA Medical Center, St. Louis, MO; and Department of Exploratory Science, Biogen, Cambridge, MA

²To whom correspondence should be addressed. E-mail: nod{at}wustl.edu.

Hedgehog (Hh) signaling plays an important role in embryonic development of many tissues, including the gastrointestinal tract. Sonic Hh–and Indian Hh–deficient mice die before or soon after birth, precluding further study of this signaling pathway in the mature intestine. Maternal transfer of inactivating monoclonal antibodies to Hh proteins (anti-Hh moAb) during late stages of embryogenesis or to early postnatal mice produced intestinal villous abnormalities, progressive runting, and severe malabsorption of dietary fat. In the present study, we sought to determine the effect of inhibiting Hh signaling on weight gain and lipid absorption in adult mice. Anti-Hh moAb was administered to adult Balb/c mice fed either a low-fat, nonpurified diet or a high-fat, semipurified diet, and to adult ob/ob mice fed the low-fat, nonpurified diet. Weight gain was significantly inhibited by anti-Hh moAb treatment in Balb/C mice fed the high-fat, but not the low-fat diet and in ob/ob mice. Further analysis of adult Balb/c mice fed the high-fat diet demonstrated that although total lipid absorption was normal, the rate of triglyceride absorption was significantly delayed in mice treated with anti-Hh moAb and they had significantly increased fecal FFA excretion. Hepatic steatosis, found in high-fat fed Balb/c mice treated with the control moAb, was abrogated by anti-Hh moAb administration. These findings point to a potential role for Hh signaling pathways in diet-induced abnormalities of lipid metabolism.

KEY WORDS: • hedgehog signaling • intestinal triglyceride absorption • hepatic steatosis

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