Obesity Prevented and Reversed in Mice By Blocking Cellular Receptor

We are beginning to understand how the blockage of the AHR prevents and reverses obesity, which may lead to a therapeutic treatment of obesity in humans.

WeightControl.com Interview with:
Craig R. Tomlinson, Ph.D.
Director of Genomics & Molecular Biology Shared Resource
Norris Cotton Cancer Center
Geisel School of Medicine at Dartmouth
Dartmouth Hitchcock Medical Center
Lebanon, NH 03756

WeightControl.com:  What is the background for this study?

Response: Obesity, a global epidemic, is a known contributor to numerous diseases, including diabetes, heart disease, and cancer. Preventing and reversing the obesity epidemic would be a critical aid in preventing and treating these diseases.

Our laboratory had discovered that a drug called NF, which was known to block the activity of a cellular receptor called the AHR, prevented obesity in mice fed a high-fat diet. We undertook studies to determine how the AHR, when inhibited by NF, exerted its effects on obesity.

WeightControl.com: What are the main findings?

Response: Our laboratory had found that a receptor found in almost all cells, called the AHR, and known primarily to combat exposures to environmental chemicals, also plays a big role in the body’s metabolism. We carried out experiments showing that when a drug named NF and known to block the AHR, was added to a high-fat diet, mice did not become any fatter than mice on a low-fat control diet. Mice on the high-fat diet with no NF became very obese within the same time span. No ill effects were observed when the drug.

We next asked whether blocking the AHR with NF could not only prevent obesity but whether NF could also reverse obesity. In these experiments, we allowed the mice to become obese on a high-fat diet, and then half the mice were switched to the high-fat diet containing the AHR blocker NF. Over the next few weeks, the mice switched to the high-fat diet containing NF dropped to the same body weight as those mice on the low-fat diet. The remaining mice on the high-fat diet became obese. Again, no ill effects were observed.

Finally, we investigated how the AHR when blocked by NF prevented and reversed obesity. It was previously known that the AHR regulates key genes in fat metabolism. We discovered that in liver cells and in fat cells, the AHR, when blocked by NF, fails to induce several key genes required for fat storage and synthesis.

In conclusion, we found that the prevention and reversal of obesity from blocking the activity of the AHR is due to key genes regulated by the AHR that are involved in fat metabolism are shut down.

WeightControl.com: What should readers take away from your report?

Response: We are beginning to understand how the blockage of the AHR prevents and reverses obesity, which may lead to a therapeutic treatment of obesity in humans. 

WeightControl.com: What recommendations do you have for future research as a result of this work?

Response: There are several key questions we are now beginning to investigate. One, what are the dietary compounds in the food we eat that activate the AHR to cause obesity; second, what role do the gut bacterial play regarding the AHR and obesity; and third and most importantly, we have initiated a clinical trial to determine whether the AHR may serve as a therapeutic target to reduce obesity in humans.

No disclosures.

Citation:

Rojas, I.Y., Moyer, B.J., Ringelberg, C.S. et al. Reversal of obesity and liver steatosis in mice via inhibition of aryl hydrocarbon receptor and altered gene expression of CYP1B1, PPARα, SCD1, and osteopontin. Int J Obes (2020) doi:10.1038/s41366-019-0512-z

https://www.nature.com/articles/s41366-019-0512-z#citeas

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