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Title: Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance

Author
item MA, XIAOJUN - Children'S Nutrition Research Center (CNRC)
item LIN, LIGEN - Children'S Nutrition Research Center (CNRC)
item YUE, JING - Children'S Nutrition Research Center (CNRC)
item PRADHAN, GEETALI - Children'S Nutrition Research Center (CNRC)
item QIN, GUIJUN - Zhengzhou University
item MINZE, LORRIE - Methodist Hospital
item WU, HUAIZHU - Baylor College Of Medicine
item SHEIKH-HAMAD, DAVID - Baylor College Of Medicine
item SMITH, C. WAYNE - Children'S Nutrition Research Center (CNRC)
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Nutrition and Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/26/2013
Publication Date: 12/23/2013
Citation: Ma, X., Lin, L., Yue, J., Pradhan, G., Qin, G., Minze, L.J., Wu, H., Sheikh-Hamad, D., Smith, C., Sun, Y. 2013. Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance. Nutrition and Diabetes. 3: e99;doi:10.1038/nutd.2013.41.

Interpretive Summary: High fructose corn syrup (HFCS) is the most commonly used sweetener in soft drinks in the United States. Some studies show that HFCS consumption correlates with obesity and diabetes (reduced insulin responsiveness), while other studies are in disagreement. The safety of HFCS consumption is an urgent public health concern which needs to be addressed. We tested mice fed (a) regular mouse diet, (b) 'Western' high-fat diet or (c) regular mouse diet supplemented with 8% HFCS in drinking water (to mimic soft drinks). We found that HFCS feeding in mice induced more severe inflammation in fat tissue than even the 'Western' diet, yielding severely reduced responsiveness to insulin. Ghrelin is a gut hormone that promotes feeding. Interestingly, we found that blocking ghrelin's action reduces HFCS-induced inflammation and increases insulin responsiveness. Our studies demonstrate that HFCS has extremely harmful effects, suggesting that dietary guidelines on HFCS consumption for Americans may need to be revisited. Blocking ghrelin may represent a novel therapy for improving insulin responsiveness, thus reducing risk for type 2 diabetes.

Technical Abstract: High fructose corn syrup (HFCS) is the most commonly used sweetener in the United States. Some studies show that HFCS consumption correlates with obesity and insulin resistance, while other studies are in disagreement. Owing to conflicting and insufficient scientific evidence, the safety of HFCS consumption remains controversial. We investigated the metabolic consequences of mice fed a (a) regular diet, (b) 'Western' high-fat diet or (c) regular diet supplemented with 8% HFCS in drinking water (to mimic soft drinks) for 10 months. Adipose tissue macrophages (ATMs) have emerged as a major pathogenic factor for obesity and insulin resistance. ATMs consist of proinflammatory F4/80+CD11c+ macrophages and anti-inflammatory F4/80+CD11c- macrophages. In this study, we assessed the effects of HFCS on ATMs in intra-abdominal fat. We found that HFCS feeding in mice induced more severe adipose inflammation and insulin resistance than even the higher-calorie-containing 'Western' high-fat diet, and these HFCS-induced deleterious effects were independent of calorie intake or body fat content. We showed that similar to 'Western' high-fat diet, HFCS triggered a robust increase of both proinflammatory ATMs and anti-inflammatory ATMs in intra-abdominal fat. Remarkably, however, the anti-inflammatory ATMs were much less abundant in HFCS-fed mice than in high-fat-fed mice. Furthermore, we showed that deletion of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) ameliorates HFCS-induced adipose inflammation and insulin resistance. HFCS-fed GHS-R-null mice exhibit decreased proinflammatory ATMs in intra-abdominal fat, reduced adipose inflammation and attenuated liver steatosis. Our studies demonstrate that HFCS has detrimental effects on metabolism, suggesting that dietary guidelines on HFCS consumption for Americans may need to be revisited. GHS-R deletion mitigates the effects of HFCS on adipose inflammation and insulin resistance, suggesting that GHS-R antagonists may represent a novel therapy for insulin resistance.