Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur.

Klebig, Mitchell; Wilkinson, John E.; Geisler, John G.; Woychik, Richard P.

doi:10.1073/pnas.92.11.4728

Cited by 264 publications

(174 citation statements)

References 39 publications

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“…In all cases, a heterologous promoter causes the normal agouti protein to be ectopically expressed in a ubiquitous manner (1,(12)(13)(14). We recently confirmed that the ectopic expression of the normal agouti protein is responsible for the obesity and insulin resistance through the production of transgenic mice that express the normal agouti gene from a ubiquitous promoter (18). However, from these experiments, we were not able to distinguish between a ubiquitous, systemic effect or a localized, tissue-specific effect of agouti.…”

mentioning

confidence: 70%

“…To generate the aP2 promoter-agouti expression construct, a HindIII-ClaI fragment containing the complete mouse agouti cDNA along with the simian virus 40 polyadenylylation signal sequence was isolated from BAPa (18). This fragment was cloned downstream of the Ϫ5.4 kb to ϩ21 bp fragment of the promoter for the adipocyte P2 (aP2) gene in the pSKIIϩ vector (24).…”

Section: Methodsmentioning

confidence: 99%

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Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

Mynatt

Miltenberger

Klebig

et al. 1997

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

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The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.

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mentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

Mynatt

Miltenberger

Klebig

et al. 1997

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

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“…In litters from Agouti/L mothers, A ypositive and A y -negative offspring are easily distinguished by their distinct coat colors. Agouti/L mice become obese around 6-8 weeks of age [15]. The body weights and blood glucose levels of Agouti/L and L mothers are shown in Table 1.…”

Section: Animalsmentioning

confidence: 99%

Long-term effect of maternal obesity on pancreatic beta cells of offspring: reduced beta cell adaptation to high glucose and high-fat diet challenges in adult female mouse offspring

Han

Epstein

et al. 2005

Diabetologia

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Aim/hypothesis: Obesity is a global problem with high risks of cardiovascular diseases, stroke and type 2 diabetes. It is well known that maternal obesity affects offspring by inducing malformation, functional abnormalities in many organs and cells, and by increased risk of obesity and type 2 diabetes. However, little is known about abnormalities induced by maternal obesity in pancreatic beta cells of offspring. Methods: We used mouse mothers with the Agouti yellow modification on a C57BL/6 background as a maternal model of normoglycaemic obesity, and produced Agouti-negative offspring. Half of the offspring were fed a high-fat diet. Offspring glucose tolerance was tested at different ages, and animals were killed at 50 weeks of age for islet function analysis. Results: Maternal obesity impaired glucose tolerance in female offspring fed a high-fat diet, and significantly reduced insulin secretion at 50 weeks of age in female offspring that had been fed a normal diet and high-fat diet. Insulin secretion and glucose potentiation from these islets were significantly reduced. Islet protein, DNA and insulin contents were increased while glyceraldehyde-3-phosphate dehydrogenase and transketolase activities were reduced in female offspring. Conclusions/interpretation: Our results indicate that maternal obesity has a long-term effect on the beta cells of female, but not of male, offspring, and leads to increased risk of gestational diabetes and type 2 diabetes in the offspring's later lives.

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“…Dominant mutations of the mouse ASP gene or the production of transgenic mice that ubiquitously express ASP from the human b-actin promoter will lead to a pleiotropic 'yellow obesity' syndrome. 24 Yellowing is the result of chronic binding of ASP to MC1R, and the obese, hyperglycaemic phenotype may be due to the interaction between ASP and MC4R. However, in a transgenic mice model using the melanocyte-specific TYRP1 gene promoter and keratinocyte-specific keratin-14 gene promoter to limit ASP gene expression in mouse skin, the overexpressed agouti protein enables the fading of mouse coat colour phenotype, while leaving the characteristics of obesity and hyperglycaemia unaffected.…”

Section: Seeing the Gene Therapy C-h Yang Et Almentioning

confidence: 99%

Seeing the gene therapy: application of gene gun technique to transfect and decolour pigmented rat skin with human agouti signalling protein cDNA

et al. 2004

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We developed a gene gun method for the transfer of human agouti signalling protein (ASP) cDNA to alter rat skin colour in vivo. Human ASP cDNA was cloned into a modified cytomegalovirus plasmid and delivered to the skin of LongEvans rats by gene gun bombardment. Skin pigmentation, body weight and blood sugar of ASP cDNA-transfected rats were recorded against the control group, which were injected with plasmids encoding for green fluorescent protein. The treated skin showed lighter skin colour after 3 days of ASP gene transfection. This depigmentation effect was most prominent on day 14 and the skin gradually returned to its original pigmentation by day 28. Successful transfection of ASP gene in skin and hair follicles, as well as downregulation of melanocortin-1 receptor (MC1R) and tyrosinase expression upon treatment, was confirmed using immunohistochemistry and Western blot analysis. Body weight and blood sugar in the treated rats did not show statistically significant differences as compared to control groups. These observations demonstrate that gene transfer using the gene gun method can induce high cutaneous ASP production and facilitate a switch from dark to fair colour without systemic pleiotropic effects. Such a colour switch may be that ASP is acting in a paracrine fashion. In addition, this study verifies that ASP exerts its functions by acting as an independent ligand that downregulates the melanocyte MC1R and tyrosinase protein in an in vivo system. Our result offers new, interesting insights about the effect of ASP on pigmentation, providing a novel approach to study the molecular mechanisms underlying skin melanogenesis.

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Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur.

Cited by 264 publications

References 39 publications

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

Long-term effect of maternal obesity on pancreatic beta cells of offspring: reduced beta cell adaptation to high glucose and high-fat diet challenges in adult female mouse offspring

Seeing the gene therapy: application of gene gun technique to transfect and decolour pigmented rat skin with human agouti signalling protein cDNA

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