A Longitudinal Hormonal Profile of the Genetically Obese Mouse*

Garthwaite, Thomas L.; Martinson, Donald R.; Tseng, Leon F.; Hagen, Thad C.; Menahan, Lawrence A.

doi:10.1210/endo-107-3-671

Cited by 114 publications

(55 citation statements)

References 36 publications

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“…The prototypical example is the obese (ob/ob) mouse. These mice are profoundly obese, hyperphagic, and diabetic and have reduced locomotor activity and metabolic rates (Garthwaite et al 1980;Mayer et al 1953;Pelleymounter et al 1995). Initial parabiosis experiments revealed that ob/ob mice lack a circulating factor produced by their wildtype litter mates (Coleman 1973(Coleman , 1978.…”

Section: Animal Models Of Obesitymentioning

confidence: 99%

Relevance of animal models to human eating disorders and obesity

2008

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Background and rationale This review addresses the role animal models play in contributing to our knowledge about the eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) and obesity. Objectives Explore the usefulness of animal models in complex biobehavioral familial conditions, such as AN, BN, and obesity, that involve interactions among genetic, physiologic, psychological, and cultural factors. Results and conclusionsThe most promising animal model to mimic AN is the activity-based anorexia rodent model leading to pathological weight loss. The paradigm incorporates reward elements of the drive for activity in the presence of an appetite and allows the use of genetically modified animals. For BN, the sham-feeding preparation in rodents equipped with a gastric fistula appears to be best suited to reproduce the postprandial emesis and the defects in satiety. Animal models that incorporate genes linked to behavior and mood may clarify biobehavioral processes underlying AN and BN. By contrast, a relative abundance of animal models has contributed to our understanding of human obesity. Both environmental and genetic determinants of obesity have been modeled in rodents. Here, we consider single gene mutant obesity models, along with models of obesigenic environmental conditions. The contributions of animal models to obesity research are illustrated by their utility for identifying genes linked to human obesity, for elucidating the pathways that regulate body weight and for the identification of potential therapeutic targets. The utility of these models may be further improved by exploring the impact of experimental manipulations on the behavioral determinants of energy balance.

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Section: Animal Models Of Obesitymentioning

confidence: 99%

Relevance of animal models to human eating disorders and obesity

2008

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“…Garthwaite, Martinson, Tseng, Hagen & Menahan (1980) have published a longitudinal hormonal profile of the obese mouse. Insulin elevation showed no age-related differences, 5-hydroxytryptamine (5-HT) was raised in the obese mouse and increased throughout life which was also true for pituitary ACTH and ,-endorphin and plasma corticosterone.…”

Section: Miscellaneous Abnormalitiesmentioning

confidence: 99%

Mouse Mutants as Models in Endocrine Research

Charlton

1984

Exp Physiol

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Although Shire (1979) has listed some forty‐eight mouse mutants of interest to the endocrinologist, this short review has concentrated upon eleven mutations which have resulted in a significant number of scientific publications over the last 4 or 5 years. The selection of references has had to be limited, but it should be possible easily to expand the list given in this review. Although the proximate cause of none of the eleven mutations has been identified with certainty, the abnormalities of function have included hormone deficiencies and receptor and post‐receptor malfunctions. It is perhaps a reflexion on our society in the 1980s, that the bulk of research has concentrated on the obese mouse. However, we still do not know the initial cause of this syndrome. The major disadvantage of the mouse to the hormone assayist lies in the small blood volume and the extreme difficulty in taking serial blood samples over a short period of time. With increased sophistication of assay techniques this may prove less daunting, but is an area where a review of the literature reveals discrepancies between laboratories, and even between data generated by the same laboratory at different times. With regard to the hormone content of endocrine tissues, the way forward for peptide‐secreting glands may be in the measurement of mRNA levels for particular hormones. Certainly the methods of recombinant‐DNA technology will yield positive information upon the aetiology and expression of some of the syndromes considered above. Organ transplantation is an area in which mutant mice have proved useful, for example gonadal, pituitary and pancreatic tissue transplantation. The grafting of neural tissue in the hpg mouse has added a further dimension to this field of research. The great infrastructure of genetical research in mice has enabled us to breed mutant genes onto different genetic backgrounds. This area of research is one which deserves to expand. The techniues of in vitro fertilization, chimera formation and embryo transfer have been used, in part, in studies on mouse mutants, and should provide technical means for further investigating gene expression. The family of dwarf mutants are ideally suited for research into the expression of genes micro‐injected into the fertilized egg (see Charlton & Cox, 1983). As new hormones are isolated and become available for study these mouse mutants may well be useful in delineating physiological functions for natural and pharmacological products. Again, the dwarf mutants would seem ideally suited for research into the synthesis and action of GRF. Mouse mutants have proved of use to biochemists and embryologists and provide fertile ground for endocrine investigations ranging from molecular genetics to membrane biophysics.

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“…However, the inhibitory potency of leptin on HPA axis reactivity becomes inverted under conditions where leptin signaling is impaired. Mice with mutations in the leptin receptor (db/db mice) exhibit an obese phenotype that is indistinguishable from that of leptin-deficient ob/ob mice, and both mice strains exhibit hypercorticosteronemia (18,27). Consistently with this, the fa/fa Zucker rat, which is a genetic animal model for leptin resistance due to a one-point mutation in the fatty allele that causes rats to have an amino acid substitution in the extracellular domain of the leptin receptor, is both obese and hyperphagic (16,17).…”

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confidence: 99%

Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization

Müller¹,

Schweitzer²,

Dominiak³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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The HPA axis is hyperactive under conditions of leptin and insulin resistance as well as after ANG II administration. We hypothesized that a hyperreactivity of the HPA axis to ANG contributes to an impaired glucose utilization in obesity, since leptin resistance and an overactive renin-angiotensin-aldosterone system are features of obesity. Zucker rats were treated with ANG via subcutaneous minipumps (0, 0.9, and 9.0 g/h; 4 wk). PA axis reactivity and glucose homeostasis were characterized after CRH treatment and during an oral glucose tolerance test (OGTT). The elevated plasma profile of corticosterone after CRH stimulation in saline-treated OZR compared with LZR confirmed that the sensitization of the PA axis depended on leptin resistance. Irrespective of the rat strain, circulating ANG levels and blood pressure were selectively increased after administration of 9 g/h ANG (high ANG). Only high ANG induced an elevation of the corticosterone and glucose response after CRH stimulation in OZR but did not affect the ACTH secretion. During OGTT, corticosterone and consequently glucose increased in OZR after high ANG, whereas the insulin secretion was decreased. In the adrenal glands of OZR, AT1A receptor mRNA levels increased after high ANG. We conclude that the impairment of glucose utilization after ANG stimulation is potentiated in leptin-resistant rats as a result of a hyperreactive PA axis, thereby confirming the functional importance of a dysregulation within the HPA axis in metabolic syndrome or obesity. The ACTHindependent stimulation of corticosterone release and the selective increase of AT 1A receptor mRNA in the adrenals of OZR indicated a sensitization of adrenals toward ANG, causing a stimulation of the PA axis.renin-angiotensin-aldosterone system; obesity; corticosterone; adrenocorticotropic hormone; diabetes IN THE PAST DECADE, symptoms clustering the metabolic syndrome, such as hypertension, insulin resistance, obesity, and dyslipidemia, have all been associated with a dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis (8). In this regard, increased plasma levels of corticosterone and ACTH in the morning, stimulated expression of hypothalamic corticotropin-releasing hormone (CRH) mRNA as well as hippocampal mineralocorticoid receptor mRNA, and a decreased glucocorticoid negative feedback sensitivity all indicate a hyperreactivity of the HPA axis in diabetes (15).Visceral fat accumulation is related to a progressive malfunction of the HPA axis with elevations of cortisol levels and failure of central feedback control by glucocorticoid receptors (7,22). The peptide hormone leptin, which is produced by adipocytes, plays an important regulatory role in the body's fat stores by inhibiting food intake and increasing energy expenditure. Leptin has inhibitory effects on the HPA axis, since the release of CRH from isolated hypothalamus is reduced, the stress-or fasting-induced stimulation of corticosterone or adrenocorticotropic hormone (ACTH) is attenuated, and both the secretion and synthesis o...

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A Longitudinal Hormonal Profile of the Genetically Obese Mouse*

Cited by 114 publications

References 36 publications

Relevance of animal models to human eating disorders and obesity

Relevance of animal models to human eating disorders and obesity

Mouse Mutants as Models in Endocrine Research

Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization

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