Hereditary Obese-hyperglycemic Syndrome Research Articles

Age-related changes in adenohypophyses of mice with the hereditary obese hyperglycemic syndrome (ob/ob) in relation to the diabetic state of the animals.

Mice with hereditary, monogenic obese-hyperglycemic syndrome (ob/ob) were shown to have smaller adenohypophyses in comparison to their normal littermates from an age of 4 weeks onward. The size of the pars intermedia of obese mice was not, however, significantly different from that of normal littermates. Morphometric criteria strongly suggest hyperactivity of the cells of the pars intermedia of obese hyperglycemic mice. The enhanced secretion of bioactive peptides of the pars intermedia may contribute to the diabetic aspects of the obese-hyperglycemic syndrome. The hyperactivity of the pars intermedia is likely to be allophenic.

Elevated hypothalamic norepinephrine content in mice with the hereditary obese-hyperglycemic syndrome.

There is evidence that hypothalamic norepinephrine (NE) plays a role in the control of appetite in the rat. Using specific and sensitive radioenzymatic assays, we determined if there was a difference in the tissue (hypothalamus, cerebral cortex and kidney) concentration of NE or of dopamine (DA) in mice with the hereditary obese-hyperglycemic syndrome (ob/ob) and their normal weight littermates, both when they were in the rapid growth phase (2--3 months of age) and when they were mature (6--7 months of age). The concentration of NE was similar in the cerebral cortex of obese and normal mice and in the kidneys of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice and in the cerebral cortex of obese and normal mice. These observations support the concept that alterations in hypothalamic NE may play a role in the obesity of ob/ob mice.

Effects of food restriction on mice with the hereditary obese-hyperglycemic syndrome

The purpose of this study was to compare the organ weights of obese-hyperglycemic (ob/ob) mice with the organ weights of their normal litter-mates. The absolute weights of the epididymal fat pads (white fat), interscapular fat pads (brown fat) and liver were greater in ob/ob mice than in normal mice. The weights of the kidneys and heart were similar in the 2 groups. The weights of the brain and testes were decreased in ob/ob mice when compared with normal mice. The weight gain of a second group of ob/ob mice was decreased by chronic food restriction resulting in a 26% reduction in weight when compared with ob/ob mice having unrestricted access to food. This substantially reduced the weight of the liver, but resulted in a minimal reduction in the weight of the epididymal fat pad. Food restriction did not alter the weight of the interscapular fat pads. It caused a relative reduction in kidney weight and a further absolute and relative reduction in testis weight.

Monoamine oxidase, catechol-O-methyltransferase, and norepinephrine levels in mice with the hereditary obese-hyperglycemic syndrome.

There is some evidence that there are abnormalities in catecholamine metabolism in patients with obesity and diabetes mellitus. In this study we determined the tissue levels of catecholamine-metabolizing enzymes (monoamine oxidase [MAO] and catechol-O-methyltransferase [COMT]) and norepinephrine (NE) in mice with the hereditary obese-hyperglycemic syndrome (ob/ob mice). The ob/ob mice have greater MAO activity in their kidneys (+ 43 per cent), testes (+ 51 per cent), and white adipose tissue (+ 87 per cent) than their normal-weight Httermates. There is no difference in MAO activity of pancreas, liver, brain, brown fat, heart, and islets of Langerhans in ob/ob and normal mice. The ob/ob mice have less COMT activity in their liver (−39 per cent) than normal mice. There is no difference in COMT activity in the kidney, testis, pancreas, and brain between ob/ob and normal mice. The Michaelis constant of kidney MAO for the tryptamine substrate is similar in normal and obese mice, suggesting that the increased MAO activity is due to a greater amount of tissue MAO rather than an altered affinity of MAO for the tryptamine substrate. The ob/ob mice have a persistent elevation in MAO activity despite eugiycemia (older mice) and a reduction in weight (caloric restriction), suggesting that the elevated MAO activity in ob/ob mice is a primary rather than a secondary disturbance. The total NE content of kidney, white fat, and brown fat is similar in ob/ob and normal mice. The islet NE content is less than 3 pg. per islet in ob/ob and normal mice.

Glycolytic and gluconeogenic enzyme activities in the hereditary obese-hyperglycemic syndrome and in acquired obesity.

Activities of hepatic “regulatory” glycolytic and gluconeogenic enzymes were assayed in obese-hyperglycemic mice and were found to be elevated over those observed in lean littermates. Qualitatively similar results were obtained when goldthioglucose-obese mice were compared with untreated controls. It therefore appears that these alterations of enzyme activity are not unique to the obese-hyperglycemic syndrome but reflect metabolic disturbances related to obesityper se. The unexpected elevation in the activities of the gluconeogenic enzymes are discussed. Glycolytic enzyme activity assayed in heart and striated muscle revealed no differences between obese-hyperglycemic mice and their lean littermates.

Pathogenetic aspects of the obese-hyperglycemic syndrome in mice (genotype obob). II. Extrapancreatic factors.

The cause of the pronounced insulin resistance of the hereditary obese-hyperglycemic syndrome in mice (obob) is so far unknown. To evaluate whether growth hormone (GH) is of pathogenetic significance in this context thein vivo incorporation of sulfate into costal cartilage was measured in obese-hyperglycemic mice and their lean littermates at various ages. It was found that a) GH administration raised the sulfation activity of the costal cartilage in both types of mice; b) the hormone further increased the insulin resistance of the obesehyperglycemic animals; c) the sulfate incorporation of the obese mice was considerably elevated after 1 month of age and remained high until the age of about 10 months. In 17 months old animals it had returned to a level similar to that of the lean littermates. In addition, the epiphyseal width of the tibia was increased in the obese mice. Since it was not clear whether the increased rate of sulfate in corporation was due to an elevated endogenous GH activity and/or the high serum insulin levels prevailing in the obese mice at this period of life a study of the pituitary morphology was carried out. The lack of obvious structural or quantitative differences between the pituitary alpha cells of the lean and obese mice did not exclude the possibility that the elevated sulfation activity was caused by the high serum insulin levels rather than an increased circulating GH activity. — Glucokinase activity, characterized by a highKm value, was found in the livers of both lean and obese mice. A significant elevation of this enzyme activity, but not of the hexokinase activity, in the obese mice strongly suggests that the insulin resistance does not extend to the liver cells in the obese-hyperglycemic syndrome.

Functional and Allometric Descriptions of the Liver and Small Intestine in Genetically Obese Mice

To assess intestinal activity in mice with the hereditary obese hyperglycemic syndrome, the small gut was studied by means of histochemistry, as well as the transport of 10-3M glucose and 5 × 10-6M L-methionine against a concentration gradient in vitro. In addition, the weight of the intestine was determined at nine and eleven weeks of age. There was no difference in the histochemical reactions of the gut between affected animals and their normal littermates. There was also no impairment of in vitro transport of the 2 nutrients. While the small gut of the obese animals weighed more than that of controls, the weight was correctly predicted by the allometric relationship on the basis of their increased body weight. The weight of the liver in the hereditary obese hyperglycemic mice was considerably greater than predicted by the allometric relationship.

Extreme sensitivity of obese hyperglycemic mice to caffeine and coffee

Mice with the hereditary obese hyperglycemic syndrome are unusually sensitive to the toxic action of caffeine. A single injection of caffeine, or the replacement of drinking water by coffee for 1 week causes a drastic and prolonged (2 or more months) elevation of blood glucose. Administration of purines and pyrimidines other than alloxan (shown previously to cause in this syndrome prolonged lowering of blood glucose and regranulation of beta cells) did not lead to striking results. No explanation for this unexpected effect of caffeine is offered.

Organ Weights in Three Forms of Experimental Obesity in the Mouse

Obesity in mice is accompanied by changes in organ weight. Certain changes, like the enlargement of the liver, heart and kidneys appear to be nonspecific effects of prolonged hyperphagia. Such changes are seen in ‘regulatory’ as well as in ‘metabolic’ obesities. Other changes may be part of a syndrome of which obesity is also a component; for example, in the hereditary obese-hyperglycemic syndrome, a metabolic form of obesity, the pancreas and the thymus are enlarged and the size of the brain decreased. These findings emphasize the need for a wider recognition of the differences between obesities of various etiologies and pathogeneses.

Electrolyte and water composition of muscle and liver in hereditary obese-hyperglycemic syndrome of mice.

Summary1. Samples of striated muscle and liver from fasted mice with the hereditary obese-hyperglycemic syndrome were analyzed for water, fat, potassium, sodium, and chloride. 2. Some degree of intracellular dehydration and a greater degree of extracellular dehydration was observed without change in concentration of intracellular potassium.

Hypercholesteremia in the hereditary obese-hyperglycemic syndrome of mice.

Hypercholesteremia in the hereditary obese-hyperglycemic syndrome of mice.

Total body water and blood volume in hereditary obese-hyperglycemic syndrome of mice.

SummaryTotal body water and blood volume were determined in mice with the hereditary obese hyperglycemic syndrome and in littermate controls. Only 12% of the excess weight of obese animals was found to be represented by water. Blood volume was not increased in obese animals. The total body water and percentage of weight represented by water in young obese animals was similar to those in non-obese animals of the same weight.

Normal iodine uptake and anoxia resistance accompanying apparent hypometabolism in hereditary obese-hyperglycemic syndrome.

SummaryIn the hereditary obese hyperglycemic syndrome of mice, radioactive iodine uptake is normal. Similarly, the anoxia test reveals no difference in dependence on oxygen tension between obese and non-obese mice. The significance of these findings is discussed with respect to the etiology of the syndrome, and to the extension of the concept of basal metabolic rate to obese animals.