Obesity is Inflammatory Disease, Rat Study Shows

Scientists led by Dr David Fairlie from the University of Queensland, Australia, have found abnormal amounts of an inflammatory protein called PAR2 in the fat tissues of overweight and obese rats and humans. PAR2 is also increased on the surfaces of human immune cells by common fatty acids in the diet. When obese rats on a diet high in sugar and fat were given a new oral drug that binds to PAR2, the inflammation-causing properties of this protein were blocked, as were other effects of the high-fat and high-sugar diet, including obesity itself.

Zucker Rat, a pet rat that has developed diabetes as a result of a genetic disorder that causes obesity. Image credit: Joanna Servaes / CC BY-SA 3.0.

Zucker Rat, a pet rat that has developed diabetes as a result of a genetic disorder that causes obesity. Image credit: Joanna Servaes / CC BY-SA 3.0.

“This important new finding links obesity and high fat, high sugar diets with changes in immune cells and inflammatory status, highlighting an emerging realization that obesity is an inflammatory disease,” Dr Fairlie said.

“Drugs designed to block certain inflammatory proteins, as in this report, may be able to prevent and treat obesity, which in turn is a major risk factor for type 2 diabetes, heart disease, stroke, kidney failure, limb amputation, and cancers.”

To make the discovery, the team discovered the first potent, selective and orally bioavailable small molecule antagonists of PAR2 and characterized their functional responses in inflammatory cellular and animal models.

They found that PAR2 expression is increased in vivo in adipose tissue from obese humans and rats, stimulated in vitro in human macrophages by the dietary fatty acid palmitic acid, and inhibited in vivo and in vitro by a PAR2 antagonist. This antagonist was then used as a tool to dissect roles for PAR2 activation in mediating metabolic dysfunction in human monocyte-derived macrophages (HMDM), human and rodent adipocytes, and diet-induced obesity in rats.

Oral treatment of diet-induced obese rats attenuated PAR2 signaling in adipose tissue and inhibited adipose inflammation, insulin resistance, diet-induced obesity and cardiovascular abnormalities.

This is the first report that a PAR2 antagonist improves obesity, glucose homeostasis and obesity-associated chronic inflammation in vivo.

The results, published in the FASEB Journal, indicate that increased PAR2 expression may be a valuable new biomarker for metabolic dysfunction and further, that PAR2 antagonism can be an effective intervention for treating metabolic dysfunction and obesity.

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Lim J et al. 2013. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J, 27: 4757-4767; doi: 10.1096/fj.13-232702