Glucose-6-phosphatase activity in the hypothalamus of the mouse (original) (raw)
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Physiology & Behavior, 1979
COSCINA. Intact regulation of protein intake during the development of hypothalamic or genetic obesity in rats. PHYSIOL. BEHAV. 23(4) 751-755, 1979.--Adult female rats made hyperphagic with bilateral lesions of the medial hypothalamus as well as spontaneously hyperphagic adult female rats of the Zucker strain were studied for their abilities to regulate dietary protein and energy intakes. This was accomplished by permitting both models of animal obesity to select freely between two isocaloric diets containing 10% vs 60% by weight casein (protein) for at least one month. Compared to appropriate control groups, both experimental groups became obese by consuming more of the low protein diet and less of the high protein diet. The overall effect of this selection pattern was an excessive intake of energy in the form of carbohydrate and fat while maintaining control levels of protein intake. These data imply that the stimulus for hyperphagia in both animal models of obesity is some physiological and/or behavioral error in energy regulation but not protein regulation.
Endocrinology, 2008
Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats. (Endocrinology 149: 3870 -3880, 2008)
Enhanced Hypothalamic Glucose Sensing in Obesity: Alteration of Redox Signaling
Diabetes, 2009
OBJECTIVE-Recent data demonstrated that glucose sensing in different tissues is initiated by an intracellular redox signaling pathway in physiological conditions. However, the relevance of such a mechanism in metabolic disease is not known. The aim of the present study was to determine whether brain glucose hypersensitivity present in obese Zü cker rats is related to an alteration in redox signaling.
The Journal of biological chemistry, 1988
Significant dephosphorylation of glucose 6-phosphate due to glucose-6-phosphatase activity in rat brain in vivo was recently reported (Huang, M., and Veech, R.L. (1982) J. Biol. Chem. 257, 11358-11363). The evidence was an apparent more rapid 3H than 14C loss from the glucose pool and faster [2-3H]glucose than [U-14C]glucose utilization following pulse labeling of the brain with [2-3H,U-14C]glucose. Radiochemical purity of the glucose and quantitative recovery of the labeled products of glucose metabolism isolated from the brain were obviously essential requirements of their study, but no evidence for purity and recovery was provided. When we repeated these experiments with the described isolation procedures, we replicated the results, but found that: 1) the precursor glucose pool contained detritiated, 14C-labeled contaminants arising from glucose metabolism, particularly 2-pyrrolidone-5-carboxylic acid derived from [14C]glutamine; 2) [14C]glucose metabolite were not quantitatively...
Physiology & Behavior, 1980
and metabolic responses of mature female rats with dietary obesity to dorsomedial hypothalamic lesions: Effects of diet palatability. PHYSIOL. BEHAV. 25(6) 911-919, 1980.-Caloric intake, body weight, obesity status (Lee Index) and incorporation of U-14 C-glucose into liver and retroperitoneal fat pad glycogen and lipid were studied in mature female rats that had received bilateral lesions or sham-operations in the dorsomedial hypothalamic nuclei (DMN) after dietary obesity was well established. Their diet consisted of a high-fat-sucrose chow mix, chocolate chip cookies and a drinking fluid of 32% sucrose in tap water. Comparable groups of DMN lesioned rats (DMNL rats) and sham-operated controls were maintained on lab chow pellets and tap water. Prior to the hypothalamic operation, the animals on the high-caloric regimen consumed significantly more calories than the rats on lab chow and also attained commensurately higher body weights and obesity indices. The bulk of the calories consumed during this time was derived from the cookies. Following DMNL, the animals maintained on lab chow became hypophagic and had lower body weights than the sham-operated rats, as has been previously reported. In rats on the high-caloric regimen, DMNL resulted in hyperphagia in comparison to all other groups. The greatest percentage of the calories during this time was derived from the high-fat-sucrose chow mix and sugar water. Correspondingly, DMNL rats on the high-caloric regimen had higher body weights and obesity indices than all other groups. At sacrifice, both a diet and lesion effect were noted in an elevated incorporation of U 14-C-glucose in both fat pad and liver lipid and glycogen. The data are interpreted to mean that (1) when a highly palatable, high-caloric diet is available, DMNL do not exert their usual hypophagic and weight-lowering effects; (2) DMNL and control rats show excessive caloric intake when both groups are fed a highly palatable, high-caloric diet in comparison to their chow-fed counterparts. However, DMNL rats fed high-caloric diet also consume significantly more than controls fed this diet; (3) This excessive caloric intake of the DMNL rats possibly predisposes these animals to exaggerated iipogenesis in liver and adipose tissue; (4) the sham-operated controls on the high-caloric regimen also show greater iipogenesis but at a level intermediate between the chow-fed controls and the DMNL rats on the high-caloric diet. Dietary obesity Dorsomedial hypothalamus Palatability Lipogenesis Glucose incorporation
Hypothalamic and pituitary catecholamine levels in genetically obese mice (obob)
Brain Research, 1977
The genetically obese (obob) mouse has been widely investigated as a possible model for human obesity and related pathology 7. The syndrome observed in the obob is characterized by overeating, adiposity, hyperglycemia, insulin resistance and impairments of thermoregulation, thyroid and reproductive function 7,19-~1. The primary defect responsible for the syndrome has yet to be discovered. Much recent work, however, has been devoted to evaluation of the hypothalamic-pituitary axis in these animals. In comparison to lean littermates, both male and female obob mice have lower levels of pituitary prolactin (PRL) z3,35. Pituitary levels of luteinizing hormone (LH) are also reported to be significantly lower in obob mice than in lean controls 36, but growth hormone (GH) and follicle-stimulating hormone (FSH) levels appear to be as high or higher in obob mice as in lean controls 23,35,36. Serum levels of PRL, LH, GH, and FSH are all reported to be lower in obob mice than in lean littermates ~a,35,3~. Furthermore, there is evidence to indicate that ACTH levels may be chronically elevated in the obob al. The observations that pituitary levels of some hormones are high while serum levels are low suggest that the obob may have deficits in both the synthesis and release of pituitary hormones. Similarities have been noted between the spontaneously obese obob mouse and animals with brain-lesion produced obesity such as the ventromedial hypothalamic rat or the gold thioglucose (GTG) injected mouseT,1L Serum GH and PRL concentrations, for example, are reported to be lower in the GTG mouse 3°,35. No naturally occurring hypothalamic lesions have been reported in the obob mousel°,~t,l'~'; however, significantly elevated levels of hypothalamic norepinephrine (NE) have recently been found 25,~n. Many studies suggest that an important function of hypothalamic monoamines is the control of pituitary hormone releasO ,a2,16,33,38. Infusions of biogenic amines have been shown to inhibit or induce the release of anterior pituitary hormones 6,28,29, 33. In addition, changes both in fluorescence of hypothalamic catecholamine-containing neurons and in the activity of related enzymes have been reported to follow alterations in endocrine states 17,2z,24.
Human molecular genetics, 2015
Glycogen storage disease type-Ia (GSD-Ia) is caused by a lack of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. We have shown that gene therapy mediated by a recombinant adeno-associated virus (rAAV) vector expressing human G6Pase-α normalizes blood glucose homeostasis in the global G6pc knockout (G6pc(-/-)) mice for 70-90 weeks. The treated G6pc(-/-) mice expressing 3-63% of normal hepatic G6Pase-α activity (AAV mice) produce endogenous hepatic glucose levels 61-68% of wild-type littermates, have a leaner phenotype, and exhibit fasting blood insulin levels more typical of young adult mice. We now show that unlike wild-type mice, the lean AAV mice have increased caloric intake and do not develop age-related obesity or insulin resistance. Pathway analysis shows that signaling by hepatic carbohydrate response element binding protein that improves glucose tolerance and insulin signaling is activated in AAV mice. In addition, several longevity factors in the calorie restriction pa...