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Role of miRNAs in brown and white adipose tissue differentiation and function

Final 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. Mammals have two types of fat: brown and white, with opposing functions. The white fat is an important regulator of the whole body homeostasis that also serves to store energy in form of triglycerides. The main function of the brown adipose tissue, or the brown fat is to catabolize lipids in order to produce heat, a function that can be induced by cold exposure. Disruption of the normal differentiation or development of the white fat causes ectopic lipid storage and severe pathology in both humans and experimental animals. Increased brown fat activity and 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 demonstrated that several miRNAs with altered expression during cold are mediating the increased brown fat differentiation. Consistent with these observations, our in vivo data suggest that the white fat browning is increased in the antimiR injected mice, or in mice with genetic inhibition of the selected miRNA, suggesting that the browning also appears in vivo. We also generated triple transgenic animals necessary for the determining the origin of the beige cells within the SAT. Finally, we developed additional novel strategies to induce the brown fat differentiation and function. Specifically, we found that transplantation of the microbiota from cold-exposed, or the caloric restricted mice to germ-free mice was sufficient to increase the insulin sensitivity of the host, and promote 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 leading to reduced obesity. 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 and reduce weight/fat gain; 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 provides a direct mechanistic link between the microbiota, the innate 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.