Activation of Hedgehog signaling prevents obesity induced by high-fat diet
There is no doubt that obesity has become a major health issue that requires personal and societal changes. Considerable literature shows that obesity causes metabolic abnormalities and increases the risk of a variety of diseases and conditions, such as high blood pressure, high cholesterol, type 2 diabetes, heart disease, stroke, and cancer. Weight loss can be a touchy subject due to various reasons. It's crucial to find effective therapies to combat obesity and related complications.
Researchers, including Dr. Fanxin Long and Yu Shi from Washington University School of Medicine (WUSM), have found that activating the Hedgehog signaling pathway can prevent weight gain in mice fed a high-fat diet. The study, titled "Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice," appeared in eLife on Dec 5, 2017.
The Hedgehog (Hh) signaling pathway is widely present in animals, such as humans and mice. Hh signaling plays key roles in embryonic development as well as tissue homeostasis. Excessive activity of Hh signaling has been implicated in a wide range of human cancers. Some scientists are trying to develop inhibitors of Hh signaling for treatment of cancer.
Hh signaling functions in multiple organ systems. Recent evidence supports that Hh signaling transcriptionally targets key adipogenic factors and inhibits fat formation. However, previous studies have mainly focused on the role of Hh signaling during embryogenesis. Its role at the adult stage remains unknown.
For the current study, the researchers mainly looked at the effect of Hh signaling on diet-induced obesity after birth. They induced the expression of genes that activate Hh signaling in the fat tissues of postnatal mice. These engineered mice did not gain weight when eating a high-fat diet, whereas control animals whose Hh signaling was not activated became obese. In addition, the engineered mice showed improved whole-body glucose tolerance and insulin sensitivity.
The researchers further explored the mechanisms by which Hh signaling inhibits fat tissue formation. The Gli family of transcription factors are known to be the effectors of Hh signaling. The researchers identified that Gli2, a member of the Gli family, was the principal mediator for Hh signaling to inhibit adipocyte (fat cell) differentiation. Hh signaling activation led to a notable decrease in the size of adipocytes.
Obesity is often associated with the size of adipocytes but not the number of them. The size of adipocytes may vary dramatically in physiological conditions, while the number of adipocytes usually stays constant through adult life. As adults, obese people do not have more fat cells than thin people, but their fat cells are larger than thin people. Simply put, adults gain weight because their adipocytes get larger; adults lose weight because their adipocytes get smaller.
Taken together, these data suggest that activation of Hh signaling suppresses diet-induced obesity and metabolic symptoms. Thus Hh signaling represents a therapeutic target for obesity and related complications. One thing should be taken into consideration is that overactivation of Hh signaling may lead to the development of cancer. It's important to find ways to properly and selectively target Hh signaling in fat tissues, according to the corresponding author of the study Dr. Long.
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