Abdominal obesity, insulin resistance, and colon carcinogenesis are increased in mutant mice lacking gastrin gene expression

Cowey, Stephanie; Quast, Michael J.; Belalcazar, L. Maria; Wei, Jingwa; Deng, Bin; Given, Randall L.; Singh, Pomila

doi:10.1002/cncr.21094

Cited by 44 publications

(23 citation statements)

References 73 publications

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“…Importantly, a significant loss in the physical activity resulted in an obese phenotype of the GAS-KO mice (Cowey et al, 2005). Reduced effects of amphetamine on prepulse inhibition of startle in GAS-KO mice has also been reported (Van den Buuse et al, 2005), suggesting an important role of brain gastrin in emotional behavior of mice.…”

Section: Discussionmentioning

confidence: 89%

Significant Increase in the Aggressive Behavior of Transgenic Mice Overexpressing Peripheral Progastrin Peptides: Associated Changes in CCK2 and Serotonin Receptors in the CNS

Deng

Singh

2007

Neuropsychopharmacol

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The gastrin precursor peptide, progastrin (PG), is secreted from enteroendocrine cells in the intestine and increased in patients with hypergastrinemia and colorectal cancers. In recent years, we and others have demonstrated an important role of PG peptides in colorectal carcinogenesis, and were surprised to note significant changes in the behaviors of transgenic mice overexpressing PGs. In the present studies, we examined emotional behaviors of transgenic mice overexpressing PG in the intestinal and peripheral circulation. Aggression, locomotor activity and anxiety-like behaviors of the homozygous transgenic (Tg/Tg) mice and the wild-type (WT) littermates were examined by intruder/resident test, open field and elevated plus maze, respectively. A significant increase in the aggression, locomotor activity, and anxiety-like behaviors was detected in the Tg/Tg vs WT mice. As CCK, CCK 2 receptors (CCK 2 R), and 5-HT 1A receptors (5-HT 1A R) in the CNS play an important role in these behaviors, possible changes in the expression of CCK and CCK 2 R and the density of CCK 2 R and 5-HT 1A R were determined by either real-time RT-PCR or autoradiography of ligand binding assays. The results suggest that the expressions of CCK and CCK 2 R were increased in the hypothalamus, and the density of CCK 2 R were increased in the hypothalamus and amygdala of Tg/Tg vs WT mice. Similarly, the density of 5-HT 1A R was increased in the hypothalamus. Our results suggest that an upregulation of the CCK response system and 5-HT 1A R in the hypothalamus of Tg/Tg mice may mediate the alterations in the observed behaviors of these mice.

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Section: Discussionmentioning

confidence: 89%

Significant Increase in the Aggressive Behavior of Transgenic Mice Overexpressing Peripheral Progastrin Peptides: Associated Changes in CCK2 and Serotonin Receptors in the CNS

Deng

Singh

2007

Neuropsychopharmacol

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“…Animal studies also find that diet-induced obesity (5-9) and some forms of genetic obesity (10)(11)(12)(13)(14)(15)(16) are associated with increased tumor susceptibility. A significant correlation between adiposity and cancer is suggestive of a direct influence of white adipose tissue on carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

Ablamunits

Cohen²,

Brazee³

et al. 2006

Cancer Research

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Obesity is typically associated with increased tumor susceptibility, whereas caloric restriction, a regimen resulting in leanness, inhibits carcinogenesis. The link between adiposity and malignancies suggests that adipose tissue may influence carcinogenesis. An adipose tissue hormone, leptin, could be procarcinogenic because it stimulates proliferation in various tissues and tumor cell lines. Leptin may contribute to the correlation between adiposity and malignancies as its levels are usually increased in obese subjects and reduced by caloric restriction. We hypothesized that leptin deficiency, despite obesity, would inhibit carcinogenesis in leptin-null ob/ob mice and tested this hypothesis in two models: (a) two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and (b) p53 deficiency. Contrary to a typical association between obesity and enhanced carcinogenesis, obese ob/ob mice developed induced skin papillomas and spontaneous p53-deficient malignancies, mostly lymphomas, similarly to their lean littermates. Surprisingly, lipodystrophic (ZIP) mice that had very little both adipose tissue and leptin were highly susceptible to carcinogenesis. Hyperphagia, hyperinsulinemia, and hyperglycemia are unlikely to have contributed significantly to the enhancement of carcinogenesis in ZIP mice because similarly hyperphagic, hyperinsulinemic, and hyperglycemic ob/ob mice had normal susceptibility to carcinogenesis. Our data suggest that, in contrast to a well-known correlation between obesity and cancer, the direct effect of adipose tissue may rather be protective. (Cancer Res 2006; 66(17): 8897-902)

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“…(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) We suspected that the metabolic disorders in Snark-deficient mice might be correlated with tumorigenesis. Furthermore, SNARK activity is reportedly upregulated under genotoxic stresses in some cell culture systems, suggesting the potential roles of SNARK in cellular stress responses.…”

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confidence: 99%

Susceptibility of Snark‐deficient mice to azoxymethane‐induced colorectal tumorigenesis and the formation of aberrant crypt foci

Tsuchihara¹,

Ogura

Fujioka³

et al. 2008

Cancer Science

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A MP-activated protein kinase is a conserved serine/threonine kinase that acts as a cellular energy sensor. Once cellular ATP is consumed, activated AMPK suppresses anabolic pathways to decrease energy expenditure and activates catabolic pathways to produce ATP.(1) Furthermore, recent studies have implicated AMPK in the regulation of whole-body metabolic homeostasis, including the regulation of food intake and energy expenditure. Based on the similarity of their kinase domains, 14 AMPKrelated kinases have been predicted in the human genome. (3,4) SNARK (encoded by the NUAK2 locus) is the fourth identified AMPK-related kinase.(5) Although several in vitro studies have suggested that metabolic stresses as well as genotoxic or osmotic stresses induce SNARK activation, the physiological roles of SNARK remain uncertain.(5-7) We established Snarkdeficient mice to clarify its in vivo function. Heterozygotic mice exhibited an increased bodyweight accompanied with fat deposition, fatty changes of the liver, and increased serum triglyceride concentration. These mice also exhibited hyperinsulinemia, hyperglycemia, and glucose intolerance. These symptoms are similar to those of human type II diabetes mellitus accompanied with obesity (K. Tsuchihara et al., manuscript in preparation, 2008).Several epidemiological studies and rodent models have addressed the relationship between colorectal tumorigenesis and obesity or obesity-related metabolic disorders. (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) We suspected that the metabolic disorders in Snark-deficient mice might be correlated with tumorigenesis. Furthermore, SNARK activity is reportedly upregulated under genotoxic stresses in some cell culture systems, suggesting the potential roles of SNARK in cellular stress responses.(6) These findings prompted us to explore the involvement of Snark in colorectal tumor formation in Snark-deficient and wild-type mice treated with AOM, a chemical carcinogen that induces ACF, colorectal adenoma, and adenocarcinoma. We then assessed the chemically induced preneoplastic and neoplastic lesions in both obese and preobese Snark-deficient mice.

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Abdominal obesity, insulin resistance, and colon carcinogenesis are increased in mutant mice lacking gastrin gene expression

Cited by 44 publications

References 73 publications

Significant Increase in the Aggressive Behavior of Transgenic Mice Overexpressing Peripheral Progastrin Peptides: Associated Changes in CCK2 and Serotonin Receptors in the CNS

Significant Increase in the Aggressive Behavior of Transgenic Mice Overexpressing Peripheral Progastrin Peptides: Associated Changes in CCK2 and Serotonin Receptors in the CNS

Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

Susceptibility of Snark‐deficient mice to azoxymethane‐induced colorectal tumorigenesis and the formation of aberrant crypt foci

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