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ERC

MIRBATWAT Report Summary

Project ID: 336607
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Mid-Term Report Summary - MIRBATWAT (Role of miRNAs in brown and white adipose tissue differentiation and function)

Obesity is a major metabolic disorder leading to various health risks and reduced life expectancy. Food intake, energy expenditure and body adiposity are homeostatically regulated, and malfunctions of this balance can cause increased fat storage and obesity. Mammals have two types of fat: brown and white, with opposing functions. The white adipose tissue (WAT) is an important regulator of the whole body homeostasis that also serves to store energy in form of triglycerides (TGs). The main function of the brown adipose tissue (BAT) is to catabolize lipids in order to produce heat, a function that can be induced by cold exposure or diet. Disruption of the normal differentiation or development of the WAT causes ectopic lipid storage and severe pathology in both humans and experimental animals. Increased BAT development leads to increased energy expenditure without causing dysfunction in other tissues, and is associated with a lean and healthy phenotype, outlining the manipulation of the fat stores as an obvious therapeutic objective.
With our research we identified miRNAs that regulate BAT differentiation, and browning of the white fat depots. We could show that several miRNAs with altered expression during cold are mediating the increased brown fat differentiation. Consistent with these observations, the preliminary results of the first in vivo inhibition suggest that the white fat is decreased in the antimiR injected mice, and suggest that the browning also appears in vivo. We are currently in process of finalizing the optimisations for the in vivo delivery. We made large progress in obtaining the triple transgenic animal necessary for the determining the origin of the beige cells within the SAT, establishing their importance in the regulation of metabolism in vivo. Finally, we started developing novel strategies to induce the brown fat differentiation and function. Specifically, we found that transplantation of the microbiota from cold-exposed mice to germ-free mice was sufficient to increase the insulin sensitivity of the host, and enable complete tolerance to cold by promoting browning of the white fat, leading to increased energy expenditure and fat mass loss. These results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand. We also established that microbiota depletion using antibiotic-treated or germ-free mice leads to development of functional beige fat within the inguinal subcutaneous and perigonal visceral adipose tissues, and promotes type 2 cytokine signaling and macrophage activation in these depots. Genetic suppression of the type 2 immune signaling was sufficient to completely revert the microbiota depletion-induced browning and metabolic improvements. This alternative beige fat and macrophage activation sheds new insights into microbiota. The impact and cross disciplinary developments of this project are several-fold: first, it brings major conceptual advance in our understanding of the beige fat development and suggests novel physiological and interventional ways to promote white fat browning; second, it characterizes the origin of the beige fat during various physiological stimuli, and it provides new insights into the miRNA importance in regulating this process; third, it defines a novel, yet not described role of the intestinal microbiota; fourth, it provides comparative analysis of the changes between several physiological stimuli that lead to browning; fifth, it will provide a direct mechanistic link between the microbiota, the type 2 immune response and the beige fat development; and sixth, it suggests manipulating the gut microbes and exploiting the mechanistic link to the beige fat development and miRNA expression as grounds for development of novel therapeutic approaches for various metabolic and feeding disorders.

Contact

Alexander Waehry, (Head of Euresearch Genève)
Tel.: +4 122 379 75 60
Fax: +41 22 379 11 80
E-mail
Record Number: 189623 / Last updated on: 2016-10-12
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