Inactivation of the Rcan2 Gene in Mice Ameliorates the Age- and Diet-Induced Obesity by Causing a Reduction in Food Intake

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 (Lepob/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.

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

“…In mice, two splice variants of Rcan2 that display distinct tissue-specific expression patterns have been identified (Mizuno et al, 2004): Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is also expressed in other tissues, such as the heart and skeletal muscle. Recently, it was reported that loss of Rcan2 function in mice did not affect their linear growth (Bassett et al, 2012), but significantly ameliorated age-and dietinduced obesity by causing a reduction in food intake (Sun et al, 2011). Using double-mutant (Lep ob/ob Rcan2 −/− ) mice, we demonstrated that Rcan2 and leptin regulate body weight through different pathways.…”

“…+/− (RBRC04891) and Rps6kb1 +/− mice (RBRC02385) were generated as described previously (Kawasome et al, 1998;Sun et al, 2011), and imported from the RIKEN BioResource Center (Tokyo, Japan). Although both of these mouse strains were reported to have been backcrossed to B6 mouse for more than ten generations in the documentation of RIKEN BioResource Center, they were further backcrossed to B6 for more than six generations after arriving at our lab.…”

“…The Rcan2 gene is involved in the regulation of body weight (Sun et al, 2011). In mice, two splice variants of Rcan2 that display distinct tissue-specific expression patterns have been identified (Mizuno et al, 2004): Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is also expressed in other tissues, such as the heart and skeletal muscle.…”

“…Using double-mutant (Lep ob/ob Rcan2 −/− ) mice, we demonstrated that Rcan2 and leptin regulate body weight through different pathways. Thus, we hypothesized that Rcan2 may increase food intake and promote weight gain through a leptin-independent pathway (Sun et al, 2011). RCAN2 was initially identified as a thyroid hormone (T3)-responsive gene in human fibroblasts (Miyazaki et al, 1996).…”

Quantitative trait loci for energy balance traits in an advanced intercross line derived from mice divergently selected for heat loss

“…It is interesting that the QTL on 520 chromosome 17 affected LIVER but not PLIVER, suggesting it may have pleiotropic effects on 521 overall body size, and in fact it also maps in a similar location to a QTL for WTFINAL. Of the 522 candidate genes listed for this chromosome 17 adiposity QTL (Table 5), Rcan2 is attractive 523 because alterations in this gene reduce diet-induced obesity and liver weight (Sun et al, 2011). 524…”