Ablation of Sax2 gene expression prevents diet‐induced obesity

Dec 4, 2010The FEBS journal

Removing the Sax2 gene stops weight gain from a high-fat diet

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Abstract

Sax2 null mutants exhibited significantly lower weight gain on a high-fat diet compared to control animals.

Sax2 gene loss in mice is associated with growth retardation and high postnatal lethality.
Food intake was comparable among wild-type, heterozygous, and null mutant mice despite differences in weight gain.
Sax2 null mutants did not develop insulin resistance and had lower leptin levels under both standard and high-fat diets.
Levels of neuropeptide Y, a key regulator of energy balance, were significantly decreased in the forebrain of Sax2 null mutants on a high-fat diet.
Sax2 gene expression may be critical for the regulation of energy homeostasis and the response to dietary changes.

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Regulation of energy homeostasis is mainly mediated by factors in the hypothalamus and the brainstem. Understanding these regulatory mechanisms is of great clinical relevance in the treatment of obesity and related diseases. The homeobox gene Sax2 is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, and in the ventral neural tube starting during early development. Previously, we have shown that the loss of function of the Sax2 gene in mouse causes growth retardation starting at birth and a high rate of postnatal lethality, as well as a dramatic metabolic phenotype. To further define the role of Sax2 in energy homeostasis, age-matched adult wild-type, Sax2 heterozygous and null mutant animals were exposed to a high-fat diet. Although food uptake among the different groups was comparable, Sax2 null mutants fed a high-fat diet exhibited a significantly lower weight gain compared to control animals. Unlike their counterparts, Sax2 null mutants did not develop insulin resistance and exhibited significantly lower leptin levels under both standard chow and high-fat diet conditions. Furthermore, neuropeptide Y, an important regulator of energy homeostasis, was significantly decreased in the forebrain of Sax2 null mutants on a high-fat diet. These data strongly suggest a critical role for Sax2 gene expression in diet-induced obesity. Sax2 gene expression may be required to allow the coordinated crosstalk of factors involved in the maintenance of energy homeostasis, possibly regulating the transcription of specific factors involved in energy balance.

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Ablation of Sax2 gene expression prevents diet‐induced obesity

Abstract

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