Paternal versus maternal transmission of a stimulatory G-protein α subunit knockout produces opposite effects on energy metabolism

Yu, Shuhua; Гаврилова, Оксана; Chen, Hui; Lee, Randy; Liu, Jie; Pacák, Karel; Parlow, A.F.; Quon, Michael J.; Reitman, Marc L.; Weinstein, Lee S.

doi:10.1172/jci8437

Cited by 145 publications

(159 citation statements)

References 61 publications

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“…The resistance to a high-fat diet suggests that Sml mice should have a higher metabolic rate compared with their wild-type littermates. Yu et al 12 reported that females with an exon 2 knockout inherited paternally consume more oxygen. Similarly, Xie et al 9 describe an XLaS knockout mutation inherited paternally (eliminating XLaS as does the Sml mutation) with reduced fat mass, increased food intake and increased metabolic rate.…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

et al. 2009

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Objective: The Gnas transcription unit located within an imprinting region encodes several proteins, including the G-protein a-subunit, Gsa, its isoform XLas and their variant truncated neural forms GsaN1 and XLN1. Gsa and GsaN1 are expressed predominantly from the maternally derived allele in some tissues, whereas XLas and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gsa and XLas, and truncated forms GsaN1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of GsaN1 and XLN1, but affects full-length Gsa and XLas, allowing us to address the role of full-length Gsa and XLas. The aim of this study was therefore to determine the metabolic phenotypes of Oed and Sml mice, and to correlate phenotypes with affected transcripts. Methods: Mice were fed standard or high-fat diets and weighed regularly. Fat mass was determined by DEXA analysis. Indirect calorimetry was used to measure metabolic rate. Glucose was measured in tolerance tests and biochemical parameters in fasted plasma samples. Histological analysis of fat and liver was carried out post mortem. Results: Oed mice are obese on either diet and have a reduced metabolic rate. Sml mice are lean and are resistant to a high-fat diet and have an increased metabolic rate. Conclusion: Adult Oed and Sml mice have opposite metabolic phenotypes. On maternal inheritance, the obese Oed phenotype can be attributed to non-functional full-length Gsa. In contrast, on paternal inheritance, Sml mice were small and resistant to the development of obesity on a high-fat diet, effects that can be attributed to mutant XLas. Thus, the neural isoforms, GsaN1 and XLN1, do not appear to play a role in these metabolic phenotypes.

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Section: Discussionmentioning

confidence: 99%

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

et al. 2009

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“…23). E1 Ϫ mice were mated with wild-type CD-1 mice (Charles River Laboratories) for several generations to place them in the same genetic background as previously studied E2 Ϫ mice (2,(17)(18)(19). Subsequent genotyping was performed by PCR of mouse tail DNA by using the common upstream primer 5Ј-GAGAGCGAGAGGAAGACAGC-3Ј and downstream primers 5Ј-TCGGGCCTCTGGCGGAGCT T-3Ј and 5Ј-AGCCCTACTCTGTCGCAGTC-3Ј, which generated 330-and 250-bp bands from the wild-type (E1 ϩ ) and E1 Ϫ alleles, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Body composition was measured by using the Minispec mq10 NMR analyzer (Bruker Optics, The Woodlands, TX). Food intake, metabolic rates (oxygen consumption rate by indirect calorimetry), and activity levels were determined as described (17).…”

Section: Methodsmentioning

confidence: 99%

“…Surviving E2 mϪ/ϩ mice became obese, hypometabolic, and hypoactive, whereas E2 ϩ/pϪ survivors had reduced adipocity, with increased metabolic rate, activity levels, glucose tolerance, insulin sensitivity, and lipid clearance (17)(18)(19). The opposite metabolic phenotypes in E2 mϪ/ϩ and E2 ϩ/pϪ mice were associated with decreased and increased urinary norepinephrine excretion, respectively, suggesting they might be due to opposite changes in sympathetic activity (17).…”

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confidence: 97%

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Alternative Gnas gene products have opposite effects on glucose and lipid metabolism

Chen

Гаврилова

Liu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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170

234

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Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein ␣-subunit (Gs␣), the G protein required for receptor-stimulated cAMP production; extralarge Gs␣ (XL␣s), a paternally expressed Gs␣ isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G s␣ undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2 m؊/؉ ) or paternal (E2 ؉/p؊ ) allele results in opposite effects on energy metabolism. E2 m؊/؉ mice are obese and hypometabolic, whereas E2 ؉/p؊ mice are lean and hypermetabolic. We now studied the effects of Gs␣ deficiency without disrupting other Gnas gene products by deleting G s␣ exon 1 (E1). E1 ؉/p؊ mice lacked the E2 ؉/p؊ phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2 ؉/p؊ phenotype appears to result from XL␣s deficiency, whereas loss of paternalspecific Gs␣ expression in E1 ؉/p؊ mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2 m؊/؉ mice, E1 m؊/؉ mice had s.c. edema at birth, presumably due to loss of maternal Gs␣ expression. However, E1 m؊/؉ mice differed from E2 m؊/؉ mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1 m؊/؉ mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1 ؉/p؊ mice. Differences between E1 m؊/؉ and E1 ؉/p؊ mice presumably result from differential effects on Gs␣ expression in tissues where Gs␣ is normally imprinted.G protein ͉ genomic imprinting ͉ pseudohypoparathyroidism

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“…Also, teleost hypothalamus is an instinctive brain center and plays significant roles in many physiological functions, such as energy metabolism (Yu et al, 2000), growth, reproduction (Foran and Bass, 1999), and stress response (Wingfield and Sapolsky, 2003). Therefore, the screening and identification of genes expressed in hypothalamus will be able to provide useful insight into the molecular mechanism of growth, reproduction, sex differentiation and sex inversion behind the grouper.…”

Section: Introductionmentioning

confidence: 99%

EST-based identification of genes expressed in the hypothalamus of male orange-spotted grouper (Epinephelus coioides)

et al. 2006

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Paternal versus maternal transmission of a stimulatory G-protein α subunit knockout produces opposite effects on energy metabolism

Cited by 145 publications

References 61 publications

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

Alternative Gnas gene products have opposite effects on glucose and lipid metabolism

EST-based identification of genes expressed in the hypothalamus of male orange-spotted grouper (Epinephelus coioides)

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