The study results further suggest that the Hh pathway in mammals determines whether adult stem cells are fated for fat or bone. The findings suggest that drugs that target the Hh pathway might prove useful for the treatment of osteoporosis, diabetes, obesity, and lipodystrophy, a disease characterized by the absence of fat, said the researchers. The findings might also explain common traits normally associated with aging, they suggest.
"As we age, two striking things tend to happen almost across the board--our bones become thinner and we gain fat," said senior author, Jonathan Graff of the University of Texas Southwestern Medical Center. "Our findings are consistent with the idea that hedgehog signaling may diminish as we get older. Drugs that stimulate the pathway could possibly help to reverse or prevent this trend, building stronger bones while reducing fat."
The researchers found that flies in which the Hh pathway in the fat bodies was overactive gained less fat than normal. Conversely, treatments that blocked the action of the Hh pathway led to an increase in the insects' fat stores.
To see whether the same pattern might hold in mammals, the team then looked to the mouse. The animals' fat cells indeed expressed genes involved in the Hh pathway. In mouse cells, treatment with an Hh protein blocked the changes normally associated with the generation of fat, while methods that blocked Hh activity caused an increase in fat.
Moreover, they found, mouse cells treated with Hh not only produced less fat, but they also began to show signs normally associated with cells destined for bone. Finally, the researchers demonstrated that components of the Hh pathway are found at lower than normal levels in genetically obese mice than in normal mice.
"These data support the notion that Hh signaling plays a conserved role, from invertebrates to vertebrates, in inhibiting fat formation and highlighting the potential of the Hh pathway as a therapeutic target for osteoporosis, lipodystrophy, diabetes, and obesity," the researchers said.
Indeed, studies have already identified small molecules able to modulate the activity of Hh proteins, suggesting that possible drugs aimed at this component of the fat pathway may already exist, and that others could be made, Graff added.
The findings "suggest that drugs designed to manipulate Hh signaling might have utility in human metabolic disease of altered adiposity, such as obesity and lipodystrophy," agreed Evan Rosen of Beth Israel Deaconess Medical Center in a commentary. But, not so fast, he added.
"Though seemingly obvious--anything that causes fewer fat cells should reduce weight gain and its consequences – this is not necessarily so." Extra calories have to go somewhere, he said. If fat formation is blocked, lipid deposits may instead build in other parts of the body, such as muscle or liver. "The 'problem' in obesity is energy balance that is out of whack, and not a surfeit of adipocytes (fat cells) per se."
Regardless of the study's therapeutic implications, the findings will nonetheless put Hh back on the map as a potentially important player in fat formation, Rosen concluded.
Jae Myoung Suh, Xiaohuan Gao, Jim McKay, Renee McKay, Zack Salo, and Jonathan M. Graff of the University of Texas Southwestern Medical Center in Dallas, Texas. This work was supported by awards to J.M.G. from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). J.M.G. is an American Cancer Society Scholar and a Leukemia and Lymphoma Society Scholar.
Suh et al.: "Hedgehog signaling plays a conserved role in inhibiting fat formation." Publishing in Cell Metabolism Vol. 3, Issue 1; January 2006; pages 25–34. DOI 10.1016/j.cmet.2005.11.012 www.cellmetabolism.org
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