The development of obesity, hyperinsulinemia, and hyperglycemia in ob/ob mice

The development of obesity, hyperglycemia, and hyperinsulinemia was examined in obese-hyperglycemic (ob/ob) mice, their lean littermates, and homozygous lean mice (+/+) between 17 days and 8 wk of age. By 4 wk of age ob/ob mice displayed many of the metabolic characteristics that are typical of the syndrome in adult animals, including elevated systemic insulin and glucose levels, increased body weight, obesity, reduced skeletal growth, and in vivo evidence of insulin resistance. In addition, 4-wk-old lean littermates of obese mice had greater body weights, increased per cent carcass lipid, and higher insulin levels than did +/+ mice of the same age that were raised under identical conditions. At 17 or 21 days of age ob/ob mice, defined by either (1) elevated carcass fat content when compared to littermates at time of killing or (2) by phenotypic expression of obesity at 6 wk of age, exhibited moderate hyperinsulinemia, hypoglycemia, reduced skeletal growth, and “obesity”, as expressed by the Lee index. The present results indicate that altered pancreatic β-cell function, obesity, and abnormalities of somatic growth all precede the onset of hyperglycemia and insulin “resistance” in ob/ob mice. Furthermore, the occurrence of these characteristics before 17 days of age suggests that the transition to laboratory diet is not essential for the expression of the ob mutation. The present data also support recent studies that have described a small but reliable effect of the ob gene on the metabolism of heterozygous lean mice.     

Adrenalectomy reduces but does not reverse obesity in ob/ob mice

Bilateral adrenalectomy (ADX) of 4-month-old ob/ob mice led to reduced rates of body weight gain, a complete cessation of fat deposition and increased percentage carcass protein and ash during a 2-month observation period after surgery. However, ADX obese mice were still heavier and had more body fat and lower concentrations of carcass protein and ash than intact sex-matched littermate lean mice at the end of the experiment. When adrenalectomy was performed in younger obese mice before the syndrome was fully expressed (23 +/- 2 days of age), body weight gain was reduced by 40 per cent and fat deposition by 50 per cent during the next 3.5 months, but each was still greater than that of littermate lean mice. Despite the lower rate of weight gain after adrenalectomy, the skeletal and lean body growth of the early ADX obese mice equalled that of both obese and lean mice fed ad libitum. When the carcass composition of early ADX obese mice was compared with that of intact obese mice which were calorically restricted to the same rate of body weight gain, the ADX group had significantly less carcass fat (28 per cent) and more protein (50 per cent) and ash (20 per cent) than the dieted obese mice. In both experiments adrenalectomy led to reduced circulating immunoreactive insulin levels, although hyperinsulinemia persisted. The present results show that adrenalectomy is an effective tool for ameliorating the severity of many aspects of the ob/ob syndrome, particularly when compared with caloric restriction, but the procedure does not entirely reverse the deranged metabolism or abnormal carcass composition of these mice.     

Effects of streptozotocin on glucose metabolism, insulin response, and adiposity in ob/ob mice.

To determine whether hyperglycemia in the obese hyperglycemic (ob/ob) mouse is related to enhanced activity of the pancreatic beta cell, streptozotocin (175 mg/kg) was injected into lean and ob/ob mice at 8 wk of age. The influence of this injection upon glucose metabolism, adipose cellularity, pancreatic morphology and immunoreactive insulin (IRI) release from isolated pancreatic islets was measured. The plasma glucose levels before and after an oral glucose load were elevated in lean and decreased in ob/ob mice 2 wk after treatment with streptozotocin. By 5 wk after this treatment, a reduced pancreatic islet size, beta cell number and a decreased pancreatic islet IRI release were present in both lean and ob/ob mice. At this time, plasma glucose was still elevated in lean, but depressed in ob/ob mice and the insulin responsiveness in muscle and adipocytes was unchanged. Hyperglycemia abates in the ob/ob mouse as hypersecretion of insulin is diminished, but these observations may not be directly related, since streptozotocin affects key metabolic activities of the livers as well as the pancreatic beta cell. The progression of obesity and status of adipose cellularity are not directly related to hyper-insulinemia, since they are not altered following streptozotocin treatment.     

Functional correlates of Na+,K+-ATPase in lean and obese (ob/ob) mice

Concentrations of Na+,K+-ATPase enzyme units are lower in skeletal muscle and liver of adult obese (ob/ob) mice than in their lean counterparts. The present studies were designed to provide information on functional correlates of Na+,K+-ATPase in ob/ob mice. Obese mice had lower potassium (K+) content in muscle and liver and higher sodium (Na+) content in muscle and liver and higher sodium (Na+) content in muscle than lean counterparts. The calculated intracellular Na+/K+ ratio in muscle of obese mice was approximately twice as high as in muscle of lean mice. Oxygen consumption was measured in mice maintained at 14 degrees, 25 degrees, or 33 degrees for 40 min and injected with 0.3 or 0.9 microgram ouabain per g body weight. Ouabain, a specific inhibitor of Na+,K+-ATPase, decreased oxygen consumption less in obese mice (12%--25%) than in lean mice (19%--38%). These results suggest that Na+ pump activity may be reduced in obese mice.     

Increased protease activity in muscles of obese- (ob/ob) mice

Muscles of genetically-obese animals exhibit decreased binding of and metabolic responses to insulin. Muscle protein catabolism was investigated by measuring the activity of alkaline, myofibril-bound protease in male (ob/ob) mice, fed ad libitum, or fasted for 5 d. Enzyme activity in the isolated myobrillar fraction was determined by the degradation of 14C-globin. Compared to the lean siblings, protease activity in the obese mice was 2.0, 1.5 and 1.3-fold higher in gastrocnemius, diaphragm and soleus muscle respectively, but without change in heart. The higher protease activity in gastrocnemius, diaphragm and soleus was associated with a parallel decrease in the weight and protein mass of the muscles. The muscles of obese mice also showed a 3 to 4-fold increase in triglyceride and a 2-fold increase in glycogen content. After 5-d starvation, the activity of protease rose in the gastrocnemius of obese mice only 1.5 fold, while it increased as much as 4 and 2 fold in gastrocnemius and diaphragm, respectively, in the lean mice. There was no significant change in heart enzyme activity. After 5-d starvation, serum insulin in obese mice fell markedly but remained still higher than that in ad libitum fed lean mice. Insulin-dependent serum metabolites, as well as adipose tissue lipoprotein lipase and hepatic enzymes related to lipogenesis and gluconeogenesis were consequently much less affected in obese mice and the prevalence of adequate insulin supply appeared to be the cause for lack of significant effect on muscle protease activity in fasting obese mice. It is suggested, therefore, that the induction of myofibrillar protease in obesity is linked to the decrease in cellular responsiveness to insulin and may also be interrelated with the intracellular metabolic adjustments to the enhanced muscle lipid availability.     

Cold acclimation of obese (ob/ob) mice: effects on skeletal muscle and bone

Obese (ob/ob) and lean mice at 4 weeks of age were housed at 23 degrees C or 14 degrees C for 4 or 8 weeks to determine effects of acclimation to mild cold on the growth of skeletal muscle, bone, and fat. Body weights at 12 weeks of age averaged 48 +/- 0.6 g and 27 +/- 1.9 g for obese mice housed at 23 degrees C and 14 degrees C and 29 +/- 0.5 g and 26 +/- 0.6 g and 26 +/- 0.6 g for lean mice housed at 23 degrees C and 14 degrees C, respectively. At 23 degrees C, muscle weights of obese mice were approximately 60% of those in lean mice. Muscles of obese mice did not grow during the first 4 weeks at 14 degrees C (4 to 8 weeks of age) but did show a small gain during the second 4 weeks (9 to 12 weeks of age) at 14 degrees C. As a result, by the end of 8 weeks at 14 degrees C, muscles of obese mice weighed only 35% to 45% as much as muscles of lean mice. Growth of the tibia and femur followed the same pattern as the muscles. Obese mice housed at 23 degrees C from 4 to 12 weeks of age contained about six times as much fat as lean mice at this age. Although exposure to 14 degrees C for 8 weeks depressed the accumulation of fat in obese mice, they still contained approximately three times the percentage body fat as lean counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated serum and antral gastrin in obese (ob/ob) mice

Elevations in serum gastrin concentration of six to seven times were found in postabsorptive 5- and 10-wk-old, but not 30- and 40-wk-old, obese mice in comparison with the appropriate lean controls. At 10 wk of age a fourfold hypergastrinemia was also evident in (ob/ob) mice denied food for 48 h. In 10-wk-old (ob/ob) mice that had eaten the same amount of food as lean mice from weaning, serum gastrin was six times that of lean controls. Antral gastrin concentration was 54% higher in fed 10-wk-old (ob/ob) mice than in lean mice. No relationship was found between alterations in serum gastrin and measures of gastrointestinal size or proliferative status. Maximal gastric acid output, expressed with respect to oxyntic mucosal dry weight, was reduced by 52% in 10-wk-old (ob/ob) mice compared with lean controls. It is concluded that the hypergastrinemia of 10-wk-old (ob/ob) mice is not caused by hyperphagia, but may be a consequence of reduced acid inhibition of gastrin release.     

Lipogenesis in vivo in lean and genetically obese (ob/ob) mice fed on diets with a high fat content

The effect of variations in the fat content of the diet on fatty acid synthesis in vivo was determined in lean and genetically obese mice, using the 3H2O incorporation technique. In both lean and obese mice the rate of fatty acid synthesis was higher between 21.00 - 22.00 h than between 09.00 - 10.00 h. When lean mice were given a high fat (low-carbohydrate) diet the rate of lipogenesis in adipose tissue and rest of carcass (whole mouse minus liver and adipose tissue) was less than in similar mice given a high-carbohydrate (low-fat) diet. In obese mice, the rate of lipogenesis in adipose tissue and rest of carcass was unaffected, but liver fatty acid synthesis was reduced. In lean mice fed on diets containing a constant percentage of carbohydrate and protein, increasing the fat content of the diet (and decreasing the proportion of cellulose) produced a decrease in fatty acid synthesis in liver, adipose tissue and rest of carcass, when the measurements were made during the night-time feeding period. During the day-time, the effect of increasing the fat content of the diet was less marked. In obese mice, dietary fat did not supress either the day-time or the post-prandial night-time rate of fatty acid synthesis. It is suggested that the hyperinsulinaemia in obese mice may be able to overcome the inhibitory effect of dietary fat on fatty acid syntheses.     

A histochemical and morphological study of skeletal muscle from obese hyperglycaemic ob/ob mice

Summary The histochemical and morphological characteristics of muscles from lean and obese hyperglycaemic ob/ob mice were compared to determine the nature of the low skeletal muscle mass of the latter. Gastrocnemius and biceps brachii muscles from obese ob/ob mice were significantly lighter than those from lean mice, whereas the weights of soleus muscles were not significantly different. The small mass of the biceps brachii muscle resulted from a decrease in diameter of the large glycolytic fast white and fast intermediate fibres and a reduction in the proportion of fast white fibres. The size and frequency of the more oxidative fast red fibres was not different. The histochemical appearance of all fibre types studied from muscles in obese mice was identical to equivalent fibres in lean mice. The fat content of muscles from obese mice was three times greater than in lean mice whereas muscle DNA concentration was similar.     

Functional and histological characteristics of skeletal muscle and the effects of leptin in the genetically obese (ob/ob) mouse

BACKGROUND: Skeletal muscle mass in genetically obese (ob/ob) mice displays a reduced mass compared with their normal lean counterpart mice. However, the functional capacity of the available skeletal muscle mass in these animals has not yet been determined. OBJECTIVE: To investigate the properties of skeletal muscle in ob/ob mice and determine the effects of leptin administration on skeletal muscle in these mice. METHODS: Following 4 weeks of i.p. leptin administration (or control treatment) anaesthetized ob/ob and lean mice had their extensor digitorum longus and soleus muscles removed, and standard measures of isometric contractile properties and fatigability were performed. Histochemistry was used to determine fibre type proportions and individual fibre areas of all muscles. RESULTS: Leptin had no effect on the morphology or function of ob/ob skeletal muscle despite reducing body mass in ob/ob mice. Force production was unaltered in obese mice. However, a significant prolongation of contraction and relaxation times were evident. Obese skeletal muscle was also more fatigue resistant. Fibre proportions displayed a more slow type profile in ob/ob skeletal muscle, and in conjunction with previous work a reduced ability to hypertrophy. CONCLUSION: Skeletal muscle from obese mice is morphologically and functionally different from lean mouse skeletal muscle. Obese muscle is very similar to skeletal muscle from aged mice, and the specific contractile properties examined appear to be determined by the fibre make-up of these muscles.     

Effect of adrenalectomy on the metabolism of glucose in obese (C57 B1/6J ob/ob) mice

The genetically obese mouse, C57 B1/6J ob/ob, has been suggested as an appropriate model for the study of obesity associated with diabetes mellitus. Employing glucose ¹⁴C(μl) as a tracer, the data presented here indicate that obese mice are able to clear glucose from the blood compartment at the same rate as their lean littermates. This was demonstrated with or without an associated cold glucose load. The abnormal glucose tolerance curves observed in the obese animals may be a result of secretion of glucose into the blood. Removal of the adrenal glands from the obese mice and their lean littermate does not impair their ability to clear a glucose load from the vascular compartment. The capacity for endogenous glucose secretion of ob/ob mice is severely curtailed by adrenalectomy, in that the glucose tolerance curves of these adrenalectomized animals become similar to those of sham-operated lean littermates. Thus, it appears that a considerable component of the hyperglycemia in ob/ob mice reflects major adrenal involvement that is activated by stress, ie, ether anesthesia and blood sampling. The hyperglycemia in ob/ob mice may reflect glucocorticoid-dependent gluconeogenesis.     

Effects of adrenalectomy on muscle fibre growth and fibre-type composition in obese-hyperglycaemic (ob/ob) and lean mice

Adrenalectomy of obese mice increases the weights of their skeletal muscles towards normal. We have investigated whether this increased growth was specific for the fast phasic muscles and white, glycolytic fibres most affected by obesity and whether the proportions of the different fibre types were restored to normal. Male obese hyperglycaemic mice (ob/ob) and lean mice were adrenalectomized at 6 weeks of age and examined 6 weeks later. In obese mice body weight gain and blood glucose were markedly decreased, although still higher than in lean mice. The weight of the heart was decreased to normal in obese mice and unaffected in lean mice. In lean mice the weights of the biceps brachii, gastrocnemius and soleus muscles increased by similar small amounts after adrenalectomy. In obese mice the fast gastrocnemius and biceps brachii recovered most in weight, the soleus somewhat less, but all remained smaller than in lean adrenalectomized mice. The increased growth of the biceps brachii in obese mice after adrenalectomy was non-specific with a similar increase in size of all fibre types, including the fast red fibres which were not affected by obesity. Fibre type proportions were not normalized by adrenalectomy of obese mice but were significantly changed in adrenalectomized lean mice. We conclude that it is possible only partially to normalize muscle weight and fibre type composition in obese mice by adrenalectomy. We suppose that its effects are manifest because of other defects such as insulin resistance and that these are not all reversed by adrenalectomy.     

Effects of thyroxine on Na+,K+-ATPase and norepinephrine turnover in brown adipose tissue of obese (ob/ob) mice

Thyroxine treatment improves some of the defective thermogenic properties of obese (ob/ob) mice. Because brown adipose tissue (BAT) is an important thermogenic organ in mice, effects of thyroxine treatment on Na+, K+-ATPase, a thyroid-hormone responsive enzyme, and on rates of norepinephrine (NE) turnover, an indicator of sympathetic nervous system activity, in BAT of lean and obese mice were evaluated. Female mice, six weeks old, were injected with approximately 4 micrograms thyroxine daily for 2 weeks. Numbers of Na+, K+-ATPase enzyme units in BAT were similar in control lean and obese mice. Thyroxine treatment increased numbers of Na+, K+-ATPase enzyme units by 60% and 100% in lean and obese mice, respectively, indicating that the BAT of obese mice was responsive to thyroxine treatment. Fractional rates of NE turnover were 75% faster in BAT of control lean mice than in obese mice. Thyroxine treatment decreased functional rates of NE turnover in BAT of lean mice by 35%, but had no effect on NE turnover in BAT of obese mice. Rates of NE turnover in heart and pancreas of control lean and obese mice were unaffected by phenotype. Although the decreases in fractional rates of NE turnover in heart (-23%) and pancreas (-11%) of lean mice in response to thyroxine injections were not statistically significant, the calculated rates of NE turnover (fractional rate of NE turnover times the NE content of the organ) in these organs of lean mice were decreased 25% to 30% (P less than 0.05) in response to thyroxine. Thyroxine injections did not affect NE turnover in either heart or pancreas of obese mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of exercise and food restriction on obesity and diabetes in young ob/ob mice

Hormone levels and body composition were examined in six-week-old C57BL/6J ob/ob mice following 25 d of limited caloric intake, voluntary exercise, or combined treatment. Pair-feeding obese mice to the daily intakes of lean mice reduced body weight gain, skeletal growth and lean body mass. Although weight gain was the same in the two phenotypes, ob/ob mice had fourfold higher rates of fat deposition. When exercise was combined with pair-feeding, skeletal and lean body growth were reduced even further and weight gain was now less than ad libitum-fed lean controls. Carcass fat accretion, however, continued to be two to three times greater. No single treatment reversed the hyperglycemia or elevated hormone production of obese mice, although slightly lower values of glucose, insulin, glucagon and corticosterone were associated with pair-feeding. When diet was combined with exercise, fasting glycemia and glucagonemia were reduced to equal the values of lean mice but insulin and corticosterone levels remained elevated. The present results show that dieted and exercised ob/ob mice continue to exhibit very high rates of fat deposition even though skeletal and lean growth are severely limited. Since fat accretion is maintained under these conditions, it appears that obese mice are not just storing excess calories as fat, but are actively regulating body fat content to levels about 30 percent higher than lean mice.     

Cold acclimation of obese (ob/ob) mice: effects of energy balance

Obese (ob/ob) and lean mice at 4 weeks of age were housed at 23 degrees C or 14 degrees C for 4 to 8 weeks to examine effects of acclimation to mild cold on energy balance. Energy intake of young lean mice increased by about 50% when housed at 14 degrees C, but energy intake of cold-acclimated obese mice increased by only 8%. Efficiency of energy retention (ratio of energy gain to energy intake) in obese mice declined from 22% +/- 1.2% at 23 degrees C to 10% +/- 1.8% after 4 weeks at 14 degrees C. Lean mice exhibited a less pronounced response to temperature; their efficiency of energy retention declined from 7% +/- 1.3% at 23 degrees C to 4% +/- 2.2% after 4 weeks at 14 degrees C. After 8 weeks of cold exposure, body weights and efficiency of energy retention became equal in obese and lean mice. Calculated heat production of cold-acclimated obese and lean mice was 40% higher than that of respective controls. Obese mice reacclimated to 23 degrees C after being kept for 4 weeks at 14 degrees C consumed the same amount of energy and were 16% more efficient than obese maintained at 23 degrees C; reacclimated lean mice consumed 12% more energy but were 53% less efficient than lean mice maintained at 23 degrees C. The results indicate that obese mice are able to increase heat production and markedly reduce their efficiency of energy retention when acclimated to mild cold but that they, unlike lean mice, rapidly revert to a high efficiency of energy retention after 4 weeks of reacclimation to 23 degrees C.     

Age-related changes in lipid and carbohydrate metabolism of the genetically obese mouse

Obese mice (C57BL/6J ob/ob) and their lean controls were studied longitudinally from immediately post-weaning until 62 wk of age, at which time the experiment was terminated. The dynamic nature of the metabolic aberrations of the obese mouse syndrome was clearly demonstrated. Obese mice were hyperinsulinemic at all ages yet the concentration of glucose in plasma was elevated only at 5-20 wk and 63 wk of age, but was similar to that of lean mice at 20-60 wk of age. Triacylglycerols accumulated in the liver of obese mice between 5 and 18 wk of age to a level that was 20-fold greater than that found in the age-matched lean control. A decreased concentration of DNA/g of liver was also found in 5-18 wk-old obese mice, indicative of an enlarged hepatocyte. With the exception of 5-wk-old animals, total DNA per liver was increased in obese mice when compared to the lean control throughout the profile. Following the peak in 18-wk-old mice, the hepatic content of triacylglycerols precipitously fell so that at 45 wk of age its concentration in obese mice was similar to that of the lean control. Plasma free fatty acid levels as well as liver glycogen content were comparable in obese mice and their lean controls throughout the profile. In obese mice older than 45 wk of age, the content of triacylglycerols in plasma was significantly lower than that of the age-matched lean control while an accumulation of liver triacylglycerols was again found in obese mice. Myocardial triacylglycerols were elevated in obese mice when compared to the lean control at all ages. The longitudinal metabolic profile of the obese mouse developed in the present study clearly demonstrates the dynamic nature of the deviations in carbohydrate and lipid metabolism in this animal model of human obesity and insulin resistance.     

Diminished epinephrine excretion in genetically obese (ob/ob) mice and monosodium glutamate-treated rats.

While numerous studies have examined sympathetic nervous system activity in experimental obesity, adrenal medullary function in this condition has received less attention. The experiments described herein evaluated adrenal medullary secretion by measurement of urinary epinephrine (Epi) excretion in genetically obese (ob/ob) mice and monosodium glutamate (MSG)-treated rats. In both male and female ob/ob mice Epi excretion was reduced 42% (P less than 0.015) and 47% (P less than 0.025), respectively, despite higher rates of urine output and excretion for other amines in obese compared to lean animals. In a similar fashion, urinary Epi was also lower in MSG-treated adult rats than in untreated controls; this reduction was out of proportion to group differences in body weight or excretion of other catecholamines. Administration of D,L-fenfluramine to mice, or dietary protein supplementation in rats, increased Epi excretion to the same extent in obese and lean animals. These findings indicate that secretion of Epi by the adrenal medulla is diminished, but is normally responsive to stimulation in these two models of animals obesity, and are thus consistent with accumulating evidence of a functional impairment in adrenal medullary secretion in animal and human obesity.     

Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.     

Pancreatic islets of obese hyperglycemic mice (ob/ob).

The development of the obesity-associated hyperglycemic syndrome in ob/ob mice, genetically determined, was observed over time by a combined functional and structural study of pancreatic islets. Islet areas increased with advancing age in ob/ob mice from 2 times at 1 month to 30 times at 6 months of age the size of lean mouse islets. Islet areas apparently increased more than pancreatic insulin content in ob/ob mice. Glucose and insulin tolerance tests were performed to study in vivo responses to glucose and insulin, respectively, in 1-, 3-, and 6-month-old mice. With ob/ob mice, glucose tolerance tests revealed more elevation of plasma glucose than in lean mice, the lean mice revealing more elevated plasma insulin than the obese mice. In insulin tolerance tests, lean mice presented marked hypoglycemia, whereas ob/ob mice revealed slightly higher plasma glucose at 1 month of age but three to four times higher amounts than that of lean mice at 6 months of age. Thus, increasing insulin resistance in ob/ob mice older than 3 months is associated with progressively increasing islet area, which contains proportionally less insulin than that of lean mouse pancreas. The data suggest that insulin resistance in ob/ob mice progressively develops up to 6 months of age and that marked islet hyperplasia is likely in response to sustained hyperglycemia, leading to hyperinsulinemia and eventual marked obesity.     

Corticosterone and tri-iodothyronine transport into brain of obese (ob/ob) mice.

Unidirectional influx of [3H]-corticosterone and [125I] 3,5,3'-tri-iodothyronine (T3) into brain, and of [3H]-corticosterone into livers, of 8-10 week old lean and obese (ob/ob) mice was measured with a bolus injection, tissue-sampling technique. Uptake of corticosterone by brain and liver of ob/ob mice was comparable to that observed in lean mice, and unaffected by corticosterone concentration in the bolus (17-32 nM or 25 microM) or by addition of lean or ob/ob mouse blood serum to the bolus injectate. Uptake of T3 by ob/ob mouse brain was lower than observed in lean mice when the bolus contained physiological concentrations of T3 (2.6-19 nM). An increase in T3 concentration in the injectate to 5 microM depressed T3 uptake by brain of lean mice, but not of ob/ob mice. Addition of blood serum from ob/ob mice to the bolus further lowered influx of T3 into the brain of lean and ob/ob mice. Even though unidirectional influx of T3 into the brain of ob/ob mice was impaired, steady-state T3 concentrations in ob/ob mice brain were similar to lean values. The enhanced sensitivity of ob/ob mice to the obesity-producing effects of glucocorticoids is not caused by an increased influx of corticosterone into brain or liver.