Depressed mood is a factor in glycemic control in type 1 diabetes.

OBJECTIVE: The diabetes literature contains conflicting evidence on the relationship between depression and glycemic control. This may be due, in part, to the fact that past studies failed to distinguish between patients with type 1 and type 2 diabetes. Because these are actually completely different diseases that are often treated differently and consequently make different demands on patients, the relationship between glycemic control and depressed mood in type 1 and type 2 diabetes was examined separately. METHODS: The relationship between Beck Depression Inventory (BDI) scores and HbA1c, as an index of long-term glycemic control, was measured in samples of 30 patients with type 1 and 34 patients with type 2 diabetes. RESULTS: Groups of patients with type 1 and type 2 diabetes did not differ in mean BDI score or HbA1c level. Correlation analysis revealed a significant positive relationship between BDI scores and HbA1c in the type 1 group (r = .44, p < .02) but not in the type 2 group (r = -0.06, p > .05). This relationship was evident throughout the entire range of BDI scores and was not restricted to scores indicative of clinical depression. Patients with type 1 diabetes who had higher HbA1c and BDI scores reported a lower frequency of home blood glucose monitoring. CONCLUSIONS: Variations in depressive mood, below the level of clinical depression, are associated with meaningful differences in glycemic control in type 1 but not type 2 diabetes. Preliminary data analysis suggests that this effect may be mediated, at least in part, by decreased self-care behaviors in patients with more depressed mood.

The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis.

The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation of intracellular cAMP levels. While beta1AR and beta2AR are broadly expressed throughout tissues of the body, beta3AR is found predominantly in adipocytes. Stimulation of the betaARs leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the betaAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective beta3AR agonists are able to prevent or reverse obesity and the loss of betaAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte betaARs in models of obesity; the physiologic impact of changes in betaAR expression on body composition and thermogenesis; and the regulation and unique properties of betaAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by beta3AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed.

Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity.

Lifestyle factors related to obesity, eating behavior, and physical activity play a major role in the prevention and treatment of type 2 diabetes. In recent years, there has been progress in the development of behavioral strategies to modify these lifestyle behaviors. Further research, however, is clearly needed, because the rates of obesity in our country are escalating, and changing behavior for the long term has proven to be very difficult. This review article, which grew out of a National Institute of Diabetes and Digestive and Kidney Diseases conference on behavioral science research in diabetes, identifies four key topics related to obesity and physical activity that should be given high priority in future research efforts: 1) environmental factors related to obesity, eating, and physical activity; 2) adoption and maintenance of healthful eating, physical activity, and weight; 3) etiology of eating and physical activity; and 4) multiple behavior changes. This review article discusses the significance of each of these four topics, briefly reviews prior research in each area, identifies barriers to progress, and makes specific research recommendations.

Diazoxide restores beta3-adrenergic receptor function in diet-induced obesity and diabetes.

We previously demonstrated that the expression and function of the adipocyte-specific beta3-adrenergic receptor (beta3AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the anti-obesity effects of beta3AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in beta3AR function. The goal of this study was to determine whether lowering insulin with the K-ATP channel agonist, diazoxide (Dz) would reverse the depressed expression and function of the beta3AR found in a model of diet-induced diabetes and obesity in C57BL/6J (B6) mice. B6 male mice were placed on either high fat (HF) or low fat experimental diets. After 4 weeks, HF-fed mice were assigned to a group: HF or HF containing disodium (R,R)-5- [2-( [2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl-1,3-benzodioxole-2,2-di carboxylate (CL; 0.001%, wt/wt), Dz (0.32%, wt/wt), or their combination (CLDz). Dz animals exhibited significantly reduced plasma insulin levels as well as increased 3pAR expression and agonist-stimulated adenylyl cyclase activity in adipocytes. CLDz was more effective in reducing percent body fat, lowering nonesterified fatty acids, improving glucose tolerance, and reducing feed efficiency than either treatment alone.

Personality correlates of glycemic control in type 2 diabetes.

OBJECTIVE: To determine whether traits of normal personality are associated with variations in glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A longitudinal cohort study was conducted using data from 105 type 2 diabetic patients in a clinical trial of a stress management intervention. Before treatment assignment, patients completed the NEO Personality Inventory, Revised, which is a questionnaire inventory measuring 5 major domains of normal personality and 30 important traits that define these domains. Glycemic control was assessed by measures of HbA1c and average blood glucose levels based on 7 days of self-monitoring at baseline and at 6 and 12 months. Relationships between personality traits and measures of glycemic control were examined by correlation and linear regression models that were adjusted for age, sex, race, duration of diabetes, medication status, and experimental treatment. RESULTS: Lower average blood glucose values at baseline were associated with higher scores for the personality domain of neuroticism and several specific traits including anxiety, angry hostility depression, self-consciousness, and vulnerability but were associated with lower scores for the trait of altruism. Results were similar for HbA1c but were not as strong. Follow-up results were similar but were less consistent. CONCLUSIONS: Personality traits may offer new insights into variations in glycemic control in patients with type 2 diabetes undergoing standard management. The relative tendency to experience fewer negative emotions and to focus on the needs of others instead of oneself could prove to be a risk factor for poor glycemic control.

Transient effects of long-term leptin supplementation in the prevention of diet-induced obesity in mice.

Low plasma leptin levels have been shown to be associated with the development of obesity in mice as well as in humans. The present study was undertaken to determine if raising plasma leptin levels of obesity-prone C57BL/6J (B6) mice to those seen in obesity-resistant A/J mice would prevent the development of diet-induced obesity. Four-week-old B6 (n = 40) and A/J (n = 10) male mice were weaned onto a low-fat (11% kcal) diet. When the animals weighed 20 g, their diets were changed to a high-fat (HF) diet (58% kcal), and a continuous infusion of leptin (0.4 mg x kg(-1) x day(-1)) or phosphate-buffered saline (control) was started using Alzet minipumps. The A/J mice were not treated but were included to monitor the efficacy of the minipumps in raising plasma leptin in B6 mice. The mice were followed for 12 weeks. Chronic treatment with leptin for 4 weeks raised plasma levels in B6 mice to that of A/J mice. Plasma leptin in B6 control mice remained significantly lower than A/J mice through week 4. By week 8, leptin levels in the B6 control group had risen and were similar to A/J mice. Although there were significant weight differences between B6 treated and B6 control groups for 2-3 weeks after pump implantation, these differences were transient. Ultimately, there were no weight differences between the B6 treated and B6 control groups. There were no differences in plasma glucose between B6 treated and control groups. Plasma insulin values were also not different between the 2 groups. There was no effect of leptin supplementation on locomotor activity or food intake in B6 mice. In summary, this study demonstrates that leptin supplementation in animals that show low plasma leptin levels in response to fat feeding may slow but does not prevent the subsequent development of diet-induced obesity.

Is there a glycemic threshold for impaired autonomic control?

OBJECTIVE: Although hyperglycemia has been recognized as a predictor of cardiovascular autonomic neuropathy in diabetic patients, the glucose threshold at which autonomic control begins to become impaired has not been evaluated. This study examined whether fasting plasma glucose (FPG) or fasting plasma insulin (FPI) is associated with reductions in baroreflex sensitivity (BRS) in healthy volunteers. RESEARCH DESIGN AND METHODS: FPG and FPI were measured after an overnight fast in 162 healthy volunteers (91 men, 71 women) who were 25-44 years of age. BRS was measured with power spectral analysis. RESULTS: Univariate analyses showed that FPG was negatively correlated with BRS (r = -0.25, P < or = 0.001) with significant reductions observed in volunteers with FPG in the upper 2 quintiles (i.e., 93-124 mg/dl). However, after adjustment for other predictors of BRS (e.g., age, blood pressure, and BMI), the relationship between FPG and BRS was no longer significant. In contrast, FPI was negatively correlated with BRS in univariate analyses (r = -0.32, P < 0.0001) as well as after covariate adjustment, with close to a 50% reduction in BRS observed in the volunteers with insulin values in the highest quintile (i.e., 16-36 microU/ml). CONCLUSIONS: These findings suggest that high normal levels of FPG are associated with reduced autonomic control secondary to the effects of aging, obesity, and elevated blood pressure on FPG levels and that elevations in FPI are associated with substantial reductions in autonomic cardiac control independent of other covariates.

Differential effects of fat and sucrose on body composition in A/J and C57BL/6 mice.

The C57BL/6 (B6) mouse is more sensitive to the effects of a high-fat diet than the A/J strain. The B6 mouse develops severe obesity, hyperglycemia, and hyperinsulinemia when fed this dietary regimen. This study was conducted to determine the effects of dietary fat and sucrose concentrations on body composition and intestinal sucrase (EC 3.2.1.48) and maltase (EC 3.2.1.20) activity in these two mouse strains. High-fat diets, regardless of sucrose content, resulted in significant weight gain, higher body fat, and lower body protein and water content in both strains of mice. The shift toward higher body fat and lower protein and water content was far greater in the B6 strain. Low-fat, high-sucrose diets resulted in lower body weight in both strains, as well as significantly greater body protein content in B6 mice. Analysis of intestinal sucrase showed that the enzyme was less active in B6 mice when the diet was high in sucrose. Both sucrase and maltase had lower activity in the presence of high dietary fat in both mouse strains. The percent reduction of intestinal enzyme activity due to dietary fat was similar in both strains. The B6 mouse exhibits disproportionate weight gain and altered body composition on a high-fat diet. This coupled with the reduced body weight and increased body protein on a low-fat, high-sucrose diet suggests that factors-relative to fat metabolism rather than sucrose metabolism are responsible for obesity.

Reversal of diet-induced obesity and diabetes in C57BL/6J mice.

We have previously shown that C57BL/6J (B6) mice develop severe obesity and diabetes if weaned onto high-fat diets, whereas A/J mice tend to be obesity and diabetes-resistant. The purpose of this study was to determine if obesity and diabetes in the B6 mouse could be completely reversed by reducing dietary fat content. After 4 months, both strains consumed more calories on a high-fat diet than on a low-fat diet, and both strains showed a higher feed efficiency (FE=weight gained/calories consumed) on the high-fat diet versus the low-fat diet. However, relative to A/J mice, B6 mice demonstrated a significantly higher FE on the high-fat diet. Hyperglycemia, hyperinsulinemia, and increased adiposity were apparent in B6 mice after 4 months on the high-fat diet regardless of whether the diet was begun at weaning or 4 months later. Correlational analyses showed that adiposity was strongly related to both insulin and glucose levels in B6 mice, but only moderately related to insulin levels in A/J mice. In obese B6 mice that were switched to a low-fat diet, obesity and diabetes were completely reversed. Adiposity, fasting glucose, and fasting insulin values in these mice were equivalent to those in B6 mice of the same age that had spent 8 months on the low-fat diet. In summary, our data show that in the B6 mouse the severity of diabetes is a direct function of obesity and diabetes is completely reversible by reducing dietary fat.

Symptoms of depression and changes in body weight from adolescence to mid-life.

OBJECTIVE: To investigate the relationship of symptoms of depression to weight changes in healthy individuals of normal weight across a follow-up of over 20 y. PARTICIPANTS AND DESIGN: College students (3885 men and 841 women) were administered a self-report depression measure in the mid-1960s. Their baseline body mass index (BMI) was calculated from their college medical records. Participants were contacted by mail in the late 1980s and asked to report their current height and weight as well as their smoking and exercise habits. Another measure of depressive symptoms was obtained from 3560 individuals at follow-up. Multiple regression models were used to relate changes in weight to depression scores while controlling for background (gender, baseline BMI and the gender by BMI interaction) and behavioral (exercise and smoking) predictors. RESULTS: The relationship between depressive symptoms and body weight change took the form of an interaction with baseline BMI (P < 0.001). Those with high baseline depression scores gained less weight than their nondepressed counterparts if they were initially lean, but more if they were initially heavy. This trend was especially strong in those with high depression scores at both baseline and follow-up. CONCLUSIONS: The findings support the hypothesis that depression exaggerates pre-existing weight change tendencies. This pattern would not have been detected by an examination of main effects alone, illustrating the need to move toward more complicated interactive models in the study of psychological factors and weight.

Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice.

Uncoupling protein 2 (UCP2) maps to a region on distal mouse chromosome 7 that has been linked to the phenotypes of obesity and type II diabetes. We recently reported that UCP2 expression is increased by high fat feeding in adipose tissue of the A/J strain of mice, which is resistant to the development of dietary obesity. More recently, a third UCP (UCP3) was identified, which is expressed largely in skeletal muscle and brown adipose tissue. The UCP2 and UCP3 genes are located adjacent to one another on mouse chromosome 7. Thus, the roles of these UCPs in both metabolic efficiency and the linkage to obesity and diabetes syndromes is unclear. For this reason, we examined the expression of UCP2 and UCP3 in white adipose tissue and interscapular brown adipose tissue and in gastrocnemius/soleus muscle preparations from the obesity-resistant A/J and C57BL/KsJ (KsJ) strains and the obesity-prone C57BL/6J (B6) mouse strain. In both KsJ and A/J mice, UCP2 expression in white fat was increased approximately 2-fold in response to 2 weeks of a high fat diet, but there was no effect of diet on UCP2 levels in B6 mice. In skeletal muscle and in brown fat, neither UCP2 nor UCP3 expression was affected by diet in A/J, B6, or KsJ mice. However, in brown fat, we observed a 2-3-fold increase in the expression of UCP1 in response to dietary fat challenge, which may be related to diet-induced elevations in plasma leptin levels. Together, these results indicate that the consumption of a high fat diet selectively regulates UCP2 expression in white fat and UCP1 expression in brown fat and that resistance to obesity is correlated with this early, selective induction of UCP1 and UCP2 and is not associated with changes in expression of UCP3.

Personality predictors of mood related to dieting.

The clinical utility of a model of normal emotional functioning (vs. psychopathology) and the moderating effects of neuroticism (N) and extraversion (E) on mood were examined during a 6-week weight-loss trial. Participants were 40 obese women who completed measures of negative affect (NA) and positive affect (PA) weekly during the diet and measures of anxiety and depression (Beck Depression Inventory [BDI]) at pre-, mid-, and postdiet. Results indicated that (a) average NA and PA were each uniquely related to postdiet BDI scores, (b) N was significantly related to NA during the diet and postdiet BDI scores, and (c) N and E interacted to predict PA during the diet. The results suggest that assessment of personality and normal mood variation may be useful additions to weight-loss intervention and research.

Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice.

Despite the fact that mutations resulting in the absence of leptin or its receptor have been associated with severe obesity and diabetes, such mutations do not appear to be responsible for most human obesity. Indeed, diet-induced obesity in animals and humans has been characterized by hyperleptinemia. This has been interpreted as evidence for leptin resistance. However, no careful longitudinal studies evaluating the role of leptin in the development of obesity exist. We report a series of studies in A/J and C57BL/6J (B/6) mice that demonstrate a direct relationship between the ability to increase plasma leptin levels in response to a high-fat diet and resistance to the subsequent development of obesity and diabetes. While leptin levels are similar in lean, low-fat-fed A/J and B/6 mice, the effects of a high-fat diet on plasma leptin differ dramatically between the two strains. After 4 weeks of high-fat feeding, leptin levels in A/J mice increased 10-fold, and this elevated level was maintained independent of weight gain throughout a 14-week feeding period. However, in B/6 mice, leptin levels remained at least twofold lower and only rose very gradually along with a significant increase in adiposity, hyperglycemia, and hyperinsulinemia. These differences in the response of leptin to diet are independent of food intake and plasma insulin levels during the 1st month of feeding. Further, we demonstrated that leptin administration did not influence the expression of the novel uncoupling protein UCP2, which also responds to dietary fat. From these results, we suggest that the response of leptin to fat feeding may be an important predictor of the development of subsequent obesity.

Metabolic and behavioral effects of a high-sucrose diet during weight loss.

In response to evidence linking obesity and high amounts of dietary fat, the food industry has developed numerous reduced-fat and nonfat food items. These items frequently derive a relatively large percentage of their energy from sugars and the effect of these sugars on weight regulation is not well known. We studied the comparative effects of high- and low-sucrose, low-fat, hypoenergetic diets on a variety of metabolic and behavioral indexes in a 6-wk weight-loss program. Both diets contained approximately 4606 kJ energy/d with 11% of energy as fat, 19% as protein, and 71% as carbohydrate. The high-sucrose diet contained 43% of the total daily energy intake as sucrose; the low-sucrose diet contained 4% of the total daily energy intake as sucrose. Twenty women aged 40.6 +/- 8.2 y (mean +/- SD) with a body mass index (in kg/m2) of 35.93 +/- 4.8 consumed the high-sucrose diet; 22 women aged 40.3 +/- 7.3 y with a body mass index of 34.93 +/- 4.4 consumed the low-sucrose diet. Mixed-design analysis of variance showed a main effect of time (P < 0.01), with both diet groups showing decreases in weight, blood pressure, resting energy expenditure, percentage body fat, free triiodothyronine (FT3), urinary norepinephrine, and plasma lipids. Small but significant interactions were found between group and time in total cholesterol (P = 0.009) and low-density lipoprotein (LDL) (P = 0.01). Both groups showed decreases in depression, hunger, and negative mood, and increases in vigilance and positive mood with time (P < 0.01). Results showed that a high sucrose content in a hypoenergetic, low-fat diet did not adversely affect weight loss, metabolism, plasma lipids, or emotional affect.

Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia.

A mitochondrial protein called uncoupling protein (UCP1) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. This pathway has been implicated in the regulation of body temperature, body composition and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and humans living in a thermoneutral environment (one where an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature), as there is little brown adipose tissue present. We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity. In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast. Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding. Finally, UCP2 maps to regions of human chromosome 11 and mouse chromosome 7 that have been linked to hyperinsulinaemia and obesity. Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli.

Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice.

Fat intake has long been associated with the development of obesity. The studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As beta 3AR agonists have been shown to acutely reduce adipose tissue mass and improve thermogenesis in genetically obese rodents, we examined whether chronic supplementation of a high fat diet with a highly selective beta 3AR agonist, CL316,243 could prevent diet-induced obesity, and whether the effect could be sustained over prolonged treatment. C57BL/6J and A/J mice were weaned onto one of three diets: low fat (10.5% calories from fat), high fat (58% calories from fat), or high fat supplemented with 0.001% CL316,243. B/6J mice gained more weight on the high fat diet than A/J mice (at 16 weeks: B/6J, 36.6 +/- 1.4 g; A/J, 32.9 +/- 0.8 g; P < 0.002; n = 10), whereas weights on the low fat diets were similar (B/6J, 29.5 +/- 0.5 g; A/J, 28.8 +/- 0.6 g; P > 0.05; n = 10). CL316,243 prevented the development of diet-induced obesity in A/J animals, but not in B/6J animals. A/J mice weighed 26.0 +/- 0.5 g at 16 weeks, whereas B/6J animals on the same diet weighed 34.1 +/- 0.8 g (P < 0.00001; n = 10), but food intake was not different between the strains throughout the study. beta-Adrenergic stimulation of adenylyl cyclase in obese B/6J mice was decreased by more than 75% in white adipose tissue and by more than 90% in brown adipose tissue (BAT). In contrast, in fat-fed A/J mice, beta-agonist-stimulated adenylyl cyclase was decreased in white adipose tissue by about 10%, whereas the activity in interscapular BAT was decreased by 50%, indicating significant retention of beta AR-stimulated activity in A/J mice compared to B/6J mice. High fat feeding was associated with decreased expression of beta 3AR and beta 1AR in white adipose tissue of both strains. However, chronic CL316,243 treatment prevented both the obesity and the decline in beta 3AR and beta 1AR messenger RNA levels in all adipose depots from A/J mice, but not B/6J mice. As CL316,243-treated A/J mice, but not B/6J mice, also showed marked uncoupling protein expression in white adipose depots, the ability of chronic CL316,243 treatment to prevent diet-induced obesity is dependent upon the elaboration of functional BAT in these regions.

Animal models provide insight into psychosomatic factors in diabetes.

OBJECTIVE: To review the literature regarding the use of animal models in research addressing psychosomatic aspects of diabetes. METHOD: We examine the key findings in animal model vs. human research in the area of stress and diabetes. Previous research has suggested that stress is a potential contributor to chronic hyperglycemia in diabetes. Stress affects metabolic activity via the stimulation of a variety of hormones that can result in elevated blood glucose levels. In patients with diabetes, due to a relative or absolute lack of insulin, stress-induced increases in glucose cannot be properly metabolized. Additionally, regulation of these stress hormones may be abnormal in diabetes. RESULTS: Human studies on the role of stress in the onset and course of type II diabetes are few and are limited by the constraints and logistics of examining life stress in humans. However, animal research allows for tight experimental control and the manipulation of factors that may contribute to the development and/or course of diabetes, such as stress, eating behavior, the nutrient content of food, and physical activity. Disease processes can be examined at a mechanistic level in animals which is typically limited in human research. CONCLUSIONS: There is a large body of animal work to support the notion that stress reliably produces hyperglycemia in type II diabetes. Furthermore, there is evidence that the autonomic nervous system plays a role in the pathophysiology of this condition in both animals and humans. Examination of eating behavior and nutrient content of food in animal models of diabetes has shed light on the role of these factors in the development of diabetes, as well as obesity. Finally, genetic research using animal models of diabetes will provide new directions for research in humans to delineate the genetic contribution to the development of diabetes.

The role of motor activity in diet-induced obesity in C57BL/6J mice.

Previous research in our laboratory has demonstrated that the C57BL/6J (B/6J) mouse has a predisposition to develop severe obesity if placed on a high-fat diet. In the present study we assessed the role of physical activity in this phenomenon. Obesity-prone B/6J and obesity-resistant A/J mice were placed on one of four diets; high fat/high sucrose, high fat/low sucrose, low fat/high sucrose, and low fat/low sucrose. After 4 months, all animals on the high-fat diets had gained more weight than animals on the low-fat diets, and this phenomenon was greatly exaggerated in B/6J mice. Despite the fact that B/6J mice gained more weight than A/J mice on high-fat diets without consuming more calories, spontaneous motor activity was elevated in B/6J mice compared to A/J mice. There was no effect of the diets on activity either within or across strains. These data suggest that predisposition to diet-induced obesity is not explainable by reduced levels of physical activity.

Pharmacologic manipulation of ob expression in a dietary model of obesity.

Mutation of the obese (ob) gene results in severe hereditary obesity and diabetes in the C57BL/6J and related strains of mice. In this study we examined the expression of the ob gene in a dietary model in which moderate obesity develops in response to fat (58% of calories from fat) without mutation of the ob gene, and in four genetic models of obesity in mice: ob/ob, db/db, tubby, and fat. Several white and brown adipose depots were examined (epididymal, subcutaneous, perirenal, and interscapular). Northern blot analysis shows that levels of ob mRNA are increased in all adipose depots examined in every model of obesity. The average fold increases were 12.0 +/ 2.1 (ob/ob), 4.8 +/- 1.5 (db/db), 2.8 +/- 0.1 (tubby), 2.4 +/- 0.3 (fat), and 2.1 +/- 0.2 (high fat diet-induced A/J). Moreover, we found that the expression of the ob gene could be manipulated by pharmacologically blocking the development of diet-induced obesity. Supplementation of a high fat diet with a beta 3-adrenergic receptor agonist (CL316,243) prevented obesity, but not hyperphagia associated with high fat feeding (body weights of high fat-fed A/J mice = 34.0 +/- 1.0 g; high fat plus CL316,243-fed mice = 26.8 +/- 0.5 g; n = 10). CL316,243-treated, high fat-fed animals contained levels of ob mRNA in all adipose depots that were equal to or less than levels in low fat-fed mice (average levels in high fat plus CL316,243-fed mice relative to low fat-fed mice: 0.93 +/- 0.09). Inasmuch as fat cell size, but not number, was increased in a previous study in diet-induced obese A/J mice, these results indicate that expression of the ob gene serves as a sensor of fat cell hypertrophy, independent of any effects on food intake.