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Friday, August 2, 2013

Pattern recognition receptors in obesity and metabolic disturbances

Highlighting the role of innate immunity in the evolution of obesity and associated metabolic disorders, Jin and Flavell deliver a concise review of mechanisms involving pattern recognition receptors that produce pathology in liver, pancreas, brain and intestinal microbiota [J Allergy Clin Immunol 2013; 132(2):287-294]. 

The authors provide a summary of the biology of the major types of pattern recognition receptors [PRR], with emphasis on toll-like receptors [TLR] and NOD-like receptors [NLR].  They discuss briefly their activity in response to pathogen infection and endogenous injury.  Several NLRs can coalesce into multiprotein complexes called inflammasomes which have proven to be importantly involved in the development of insulin resistance. 

Jin and Flavell review PRR mechanisms in five critical physiologic areas: brain, pancreatic islet, and vascular inflammation, induction of peripheral insulin resistance, and disruption of intestinal microbiota homeostasis.  They note that PRRs can directly mediate and sustain inflammation in response to excessive nutrient resulting in abnormal lipid metabolism and insulin resistance in multiple tissues, which accounts for comorbidities such as type 2 diabetes and atherosclerosis.

In the gut, the authors point out that PRRs are critical to sensing and regulating the microbiota as well as responding to pathogenic insult.  TLR/NLR deficiency-associated microbial imbalance has been associated with obesity risk, insulin resistance, and fatty liver.  Interestingly, transplantation of abnormal microbiota from obese mice into wild-type mice results in reproduction of the obese metabolic phenotype that can be corrected by antibiotic treatment.  This points to a causal relationship between disrupted intestinal microbiota and the development of metabolic syndrome. 

Regarding the recent AMA announcement that obesity is a disease as opposed to lifestyle that results in a disease state, I think this is supported by findings from basic research that the development of obesity is not simply due to a lifestyle exemplified by overeating and inactivity, but also profoundly impacted by intrinsic genetic factors in metabolic system, immune system and intestinal microbial ecosystem. Recognizing obesity as a disease will help the community pay more attention to this emerging health issue and also hopefully stimulate research to understand the complex pathophysiology of obesity.

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