A mammalian homolog of Inscuteable involves in the regulation of energy homeostasis in mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 685-694-Mechanisms of Obesity
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-687
Yuko Noguchi*1, Masatoshi Nomura1, Sachiko Kamakura2, Hideki Sumimoto2 and Ryoichi Takayanagi1
1Kyushu Univ, Fukuoka, Japan, 2Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
Asymmetric cell division, which includes cell polarization, is essential for deciding cell fate concerning orientation, proliferation, and differentiation during developmental morphogenesis. Cell polarity also plays a fundamental role in cellular function including neuronal transmission and immune system. Inscuteable, a Drosophila polarity protein, functions in asymmetric cell division of neuroblast by tethering its partner Pins to Bazooka. A mammalian homolog of inscuteable (mInsc) is also shown to involve in asymmetric cell division in neuroblast, retina, lung and some cell types. Recently, forebrain-specific mInsc ablation and overexpression studies have shown that mInsc is required for the orientation of cell division in the developing cortex in mice.(1) However, those mice are viable and fertile with no gross abnormality, remaining the role of mInsc in mammals largely unknown. Recently, mice lacking AGS3, a mInsc-binding protein, has been shown to exhibit a lean phenotype due to increased energy expenditure, suggesting a possible interaction between cell polarization and metabolic signals.(2) An analysis of the mRNA expression of mInsc revealed strong expression was observed in the liver as well as in the brain. In order to analyze the functional role of mInsc in energy metabolism, null mutants of mInsc (mInsc-/-) were generated. Surprisingly, mInsc-/- mice showed a lean phenotype with reduced fat mass even on normal chow. The body weight of mInsc-/- mice was significantly lower than that of wild-type mice from 4 weeks onward. The size of adipocyte in mInsc-/- mice was significantly smaller than that in control mice. In consistent with this, mInsc-/- mice showed improved insulin and glucose tolerance. To investigate the mechanism governing the lean phenotype, metabolic measurements were performed. There is no significant difference in food consumption and locomotor activity. However, oxygen consumption during active dark cycle in mInsc-/- mice showed a trend of increase, indicating that higher energy expenditure may contribute to the decrease in body weight in mInsc-/- mice. Interestingly, the expression of Ucp1, a key regulator of energy expenditure, in brown adipose tissue was significantly increased in mInsc-/- mice. Together, we provide a compelling evidence that mInsc play an important role in energy homeostasis. mInsc and other regulatory proteins may thus be targets for intervention of obesity and related metabolic syndrome.

(1) Maria Pia Postiglione et al., Neuron 2011; 72, 269 (2) Joe B. Blumer et al., Endocrinology 2008; 149(8):3842

Nothing to Disclose: YN, MN, SK, HS, RT

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