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Montreal team discovers new molecular pathway key to understanding fat/cancer links

September 29, 2016

fat tissue

A new publication from the TFRI-funded team at McGill University (Goodman Cancer Centre) studying oncometabolism and molecular pathways
is bringing new hope to the battle against obesity, cardiovascular disease and diabetes with the significant discovery of a new molecular pathway that has the ability to turn fat storage cells into fat burning cells.

Published in Genes and Development (April 2016), the paper details how knocking out the tumour suppressor protein folliculin (FLCN) (which also helps regulate fat cells) in mice triggers a series of biomolecular signals that switch the cells from storing adipocytes to burning them.

Obesity is a major health challenge around the globe, and is a major risk factor for metabolic disorders such as Type 2 diabetes, cardiovascular diseases and certain cancers. Scientists have long accepted the concept of white and brown fat cells: where white fat is deemed unhealthy and works as energy storage tissue while brown fat mainly burns energy to produce heat and keep body temperature constant. Beige fat has also been recently discovered, and functions somewhere in between white and brown fat. Conversion from white fat cells to beige or brown fat cells is a very desirable effect in obesity,and diabetic and metabolic syndrome indications, since excess energy in the body is not stored in fat tissue; it is burned in brown or beige fat tissue.

The present study demonstrated that Flcn deletion in adipose tissue results in activation of an AMPK/PGC-1α/ERRα molecular axis, promoting mitochondrial biogenesis, oxygen consumption, FAO, UCP expression and heat production, thereby shifting white adipocytes from “lipid storage compartments” to active sites of lipid metabolism.

Further, deletion of Flcn in mouse adipose tissues leads to a complete metabolic reprogramming of both white and brown adipocytes, leading the mice to exhibit significantly higher energy expenditure associated with an increase in mitochondrial respiration.

In a nutshell, mice without Flcn stayed slim and burned more fat as energy as the fat storage units turned into fat burning engines through the stimulation of beige and brown fat pathways. The discovery of the folliculin pathway lays the groundwork for new medications to be developed that will stimulate the ‘browning’ process, potentially reducing the risk of obesity, cardiovascular disease, and diabetes.

Study: Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

Authors: Ming Yan, Étienne Audet-Walsh, Sanaz Manteghi,Catherine Rosa Dufour, Benjamin Walker, Masaya Baba, Julie St-Pierre, Vincent Giguère, and Arnim Pause.

Funding: This work was funded by the Kidney Foundation of Canada KFOC100021 (A.P.), the Myrovlytis Trust (A.P.), a Terry Fox Research Institute Program Project Team Grant on Oncometabolism (116128), the New Innovation Fund CFI 21875, CIHRMOP-125885 (V.G.), and McGill University. This work was funded by the Kidney Foundation of Canada KFOC100021 (A.P.), the Myrovlytis Trust (A.P.), a Terry Fox Research Institute Program Project Team Grant on Oncometabolism (116128), the New Innovation Fund CFI 21875, CIHR MOP-125885 (V.G.), and McGill University.

 TFRI Links, Fall 2016



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