Obesity: in the Brain or the Gut?

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Science  02 Feb 2007:
Vol. 315, Issue 5812, pp. 575
DOI: 10.1126/science.315.5812.575c

Although some blame high-fat foods for the global spread of obesity, the mechanistic connection is not solid. The hormone leptin regulates body weight by binding to receptors in the hypothalamus and initiating signaling via JAK2, STAT3, and PI3K transducer molecules. JAK2 is a cytoplasmic tyrosine kinase and is the target of several regulators, including the SH2-B family. Mice whose SH2B1 is systemically knocked out become leptin-resistant and obese and develop type 2 diabetes. Ren et al. have found that if SH2B1 is restored specifically to neural tissues, the obese mice stop overeating, the hyperlipidemia is corrected, the leptin sensitivity is restored, and the obesity reverses. Nevertheless, therapeutic targeting of this signal may not be a simple matter if, as suggested by Ley et al. and Turnbaugh et al., obesity can be mediated by members of the gut flora. It appears that obese mice and humans have a greater proportion of Firmicutes in their gut flora and that they extract energy from food more efficiently (because of the bacterial capacity for breaking down indigestible polysaccharides) than the Bacteroidetes group that dominates the flora of lean mice and people. Moreover, obesity in mice can be induced by infection. — CA

J. Clin Invest. 10.1172/JCI29417 (2007); Nature 444, 1022; 1027 (2007).

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