Inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake

PLoS One. 2011 Jan 27;6(1):e14605. doi: 10.1371/journal.pone.0014605.

Abstract

Obesity is a serious international health problem that increases the risk of several diet-related chronic diseases. The genetic factors predisposing to obesity are little understood. Rcan2 was originally identified as a thyroid hormone-responsive gene. In the mouse, two splicing variants that harbor distinct tissue-specific expression patterns have been identified: Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is expressed in the brain and other tissues such as the heart and skeletal muscle. Here, we show that Rcan2 plays an important role in the development of age- and diet-induced obesity. We found that although the loss of Rcan2 function in mice slowed growth in the first few weeks after birth, it also significantly ameliorated age- and diet-induced obesity in the mice by causing a reduction in food intake rather than increased energy expenditure. Rcan2 expression was most prominent in the ventromedial, dorsomedial and paraventricular hypothalamic nuclei governing energy balance. Fasting and refeeding experiment showed that only Rcan2-3 mRNA expression is up-regulated in the hypothalamus by fasting, and loss of Rcan2 significantly attenuates the hyperphagic response to starvation. Using double-mutant (Lep(ob/ob) Rcan2(-/-)) mice, we were also able to demonstrate that Rcan2 and leptin regulate body weight through different pathways. Our findings indicate that there may be an Rcan2-dependent mechanism which regulates food intake and promotes weight gain through a leptin-independent pathway. This study provides novel information on the control of body weight in mice and should improve our understanding of the mechanisms of obesity in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animal Feed
  • Animals
  • Body Weight
  • Eating / genetics*
  • Intracellular Signaling Peptides and Proteins
  • Leptin / physiology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Obesity / etiology*
  • Obesity / prevention & control
  • Proteins / genetics*

Substances

  • Dscr1l1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Leptin
  • Proteins