Frank Obesity Research Articles

Prevalence of vitamin D deficiency among patients visiting a tertiary care centre

Background: Heart rate variability (HRV) as a measurement of autonomic function assumes great clinical importance. It is well known that particular patterns of body fat distribution increase coronary heart disease risk both in adults and children. While frank obesity is associated with reduced HRV, indicative of poorer autonomic nervous system (ANS) function, the association between body mass index (BMI) and HRV is less clear. The dynamic autonomic responses during exercise can be measured to give actionable information for training by analysis of the ECG to determine heart rate variability. While application of HRV has been applied to predict sudden cardiac death and diabetic neuropathy in assessing disease progression. The study revealed the changes in HRV in resting condition and also after a single bout of sub maximal treadmill exercise (50% of VO2 max.) among males and females in the age group of 17-25 years at rest, and the correlations between the HRV parameters at rest and after the exercise with BMI and WHR in the subjects. An observational cross sectional study was conducted in the Physiology Department of R.G.Kar Medical College, Kolkata, India on 60 subjects (n=60) of both sexes (30 males and 30 females) in the 17-25 years age, participated in this study. Their WHR and BMI were measured and HRV was recorded during rest and immediately after exercise by digital Polyrite. Result showed that the HRV of male were more than in female in resting condition. After submaximal exercise the HRV value of males were more than their respective resting HRV values though it was not significant and, in the females, post-exercise HRV was significantly more than their respective resting HRV. This study shows that females have higher parasympathetic activity than males. There is an association between WHR and BMI and HRV in healthy female persons, which shows that there is an increase in LF/HF(low frequency and high frequency) of values among males and females after a single bout of submaximal exercise though not significant in case of males but significant in case of females.

Metabolic Syndrome Predisposes to Osteoarthritis: Lessons from Model System.

The present study aims to assess for temporal changes in tibial subchondral bone and cartilage in WNIN/Gr-Ob rats (portraying obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, hypertension) in comparison with Wistar controls (WNIN) using anthropometry, micro-computed tomography (micro-CT), scanning electron microscopy (SEM), histopathology, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Body weight, abdominal circumference, body mass index (BMI), lean/fat mass, serum tumor necrosis factor (TNF)-α levels were measured (ELISA), followed by ultrastructural analysis of tibial subchondral bone (micro-CT) and cartilage architecture (histopathology and SEM) in WNIN/Gr-Ob and WNIN rats with age (3, 6 and 9 months). Additionally, primary cultures of articular chondrocytes isolated from 6-month-old WNIN/Gr-Ob and WNIN rats were assessed for matrix metalloproteinase (MMP)-13 and Collagen type II (COL2A1) by immunofluorescence. WNIN/Gr-Ob rats exhibited frank obesity with increased BMI, lean and fat mass vis-à-vis significantly higher levels of serum TNF-α (6>9>3 months) as compared with the controls. With an increase in BMI, WNIN/Gr-Ob rats presented with tibial cartilage fibrillation, erosion, osteophyte formation (6 months) and subchondral bone cyst (9 months) confirmed by histology and SEM. An increase in subchondral trabecular bone volume (sclerosis with decreased plate porosity) was observed in all ages in WNIN/Gr-Ob rats compared to their Control. Gaining insights, primary cultures of articular chondrocytes complemented with altered cellular expressions of COL2A1 and MMP-13 from WNIN/Gr-Ob rats, indicating osteoarthritis (OA) progression. Multiple metabolic perturbations featured in WNIN/Gr-Ob rats were effective to induce spontaneous OA-like degenerative changes affecting knee joints akin to human OA.

Excess Body Weight, Insulin Resistance and Isolated Systolic Hypertension: Potential Pathophysiological Links.

Isolated systolic hypertension, the most common form of hypertension in the elderly, but also detectable among young and middle-aged subjects, is independently associated with higher risk of cardiovascular events and all-cause mortality. Among various pathophysiological changes associated with aging, excess body weight and insulin resistance may predispose to this type of hypertension. Overweight or frank obesity and their frequent companion insulin resistance could mediate the development of isolated systolic hypertension through increase in the renin-angiotensin-aldosterone system activity, in the sympathetic tone and in salt-sensitivity, all in turn leading to endothelial dysfunction, arterial stiffness and increase in blood pressure. This review will focus on this cluster of pathophysiological factors and on the mechanistic pathways whereby they may favor the development of isolated systolic hypertension.

Male Brown Fat-Specific Double Knockout of IGFIR/IR: Atrophy, Mitochondrial Fission Failure, Impaired Thermogenesis, and Obesity.

It is unknown how the lack of insulin receptor (IR)/insulinlike growth factor I receptor (IGFIR) in a tissue-specific manner affects brown fat development and mitochondrial integrity and function, as well as its effect on the redistribution of the adipose organ and the metabolic status. To address this important issue, we developed IR/IGFIR double-knockout (DKO) in a brown adipose tissue-specific manner. Lack of those receptors caused severe brown fat atrophy, enhanced beige cell clusters in inguinal fat; loss of mitochondrial mass; mitochondrial damage related to cristae disruption; and the loss of proteins involved in autophagosome formation, mitophagy, mitochondrial quality control, and dynamics and thermogenesis. More important, DKO mice showed an impaired thermogenesis upon cold exposure, based on a failure in the mitochondrial fission mechanisms and a much lower uncoupling protein 1 transcription rate and content. As a result, DKO mice under normal conditions showed an obesity susceptibility, revealed by increased body fat mass and insulin resistance. Upon consumption of a high-fat diet, DKO mice displayed frank obesity, as shown by increased body weight, increased adiposity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia, all consistent with a metabolic syndrome. Collectively, our data suggest a cause-and-effect relationship between failure in brown fat thermogenesis and increased adiposity and obesity.

The critical role of cognitive-based trait differences in transcranial direct current stimulation (tDCS) suppression of food craving and eating in frank obesity

Obesity remains a major public health concern and novel treatments are needed. Transcranial direct current stimulation (tDCS) is a neuromodulation technique shown to reduce food craving and consumption, especially when targeting the dorsolateral prefrontal cortex (DLPFC) with a right anode/left cathode electrode montage. Despite the implications to treat frank (non-bingeeating) obesity, no study has tested the right anode/left cathode montage in this population. Additionally, most tDCS appetite studies have not controlled for differences in traits under DLPFC control that may influence how well one responds to tDCS. Hence, N = 18 (10F/8M) adults with frank obesity completed the Dutch Eating Behavior Questionnaire-Restraint and Barratt Impulsiveness Scale, and received 20 min of 2 mA active tDCS and control tDCS session. Craving and eating was assessed at both sessions with a food photo “wanting” test and in-lab measures of total, preferred, and less-preferred kilocalories consumed of three highly palatable snack foods. While main effects of tDCS vs. control were not found, significant differences emerged when trait scores were controlled. tDCS reduced food craving in females with lower attention-type impulsiveness (p = 0.047), reduced preferred-food consumption in males with lower intent to restrict calories (p = 0.024), and reduced total food consumption in males with higher non-planning-type impulsiveness (p = 0.009) compared to control tDCS. This is the first study to find significant reductions in food craving and consumption in a sample with frank obesity using the most popular tDCS montage in appetite studies. The results also highlight the cognitive-based heterogeneity of individuals with obesity and the importance of considering these differences when evaluating the efficacy of DLPFC-targeted tDCS in future studies aimed at treating obesity.

The Critical Role of Individual Trait Differences in Transcranial Direct Current Stimulation Outcomes: Effects in a Sample with Non Binge‐Eating Obesity

BackgroundObesity is a major public health concern and effective treatments for the disease are lacking. Transcranial direct current stimulation (tDCS) is a non‐invasive, neuromodulation technique that reduces food craving and consumption, especially when using a right‐anode/left‐cathode (RA/LC) montage targeting the dorsolateral prefrontal cortex (DLPFC). Despite the implications of these findings to treat frank (non‐binge‐eating) obesity, no study has tested RA/LC tDCS on this population. Moreover, most tDCS studies on appetite have not considered the potential influence of sex or of individual differences in psychological traits that are under the control of the DLPFC when evaluating the efficacy of tDCS on appetite variables.ObjectiveThis study tested the hypothesis that tDCS reduces food consumption and craving in frank obesity and that sex and individual trait differences influence these effects.MethodsN=18 (10F/8M) adults with frank obesity (BMI ≥ 30 with no binge‐eating) completed the Dutch Eating Behavior Questionnaire‐Restraint and Barratt Impulsiveness Scale. Both have subscales related to cognitive inhibition, a putative functional mechanism underlying tDCS effects on appetite. Participants received 20 minutes of 2mA tDCS and a sham session. Total and preferred‐food consumption was assessed with an in‐lab eating test and craving was assessed with a food photo “wanting” test.ResultsThe effect of tDCS on food consumption or craving did not differ from sham. However, significant differences emerged when sex and psychological trait scores were controlled. tDCS vs. sham reduced food craving in individuals with lower attention‐type impulsiveness (p=0.043), total kilocalories consumed in males with lower non‐planning‐type impulsiveness (p=0.009), and preferred‐food kilocalories consumed in males with lower intent to restrict calories (p=0.024).ConclusionThis is the first study to find significant changes in food craving and consumption in a population with frank obesity with the most popular tDCS montage used in appetite studies. The findings also highlight the psychological heterogeneity of individuals with obesity and the importance of identifying these and sex differences in future tDCS studies aimed at treating obesity.Support or Funding InformationNIH‐T32Pre‐Doctoral training grant to MKR made possible by UAB's Nutrition Obesity Research Center.

Cardiovascular risk factors, anxiety symptoms and inflammation markers: Evidence of association from a cross-sectional study

IntroductionAnxiety disorders and Cardiovascular (CV) diseases, among the most common disorders in Western World, are often comorbid. A chronic systemic inflammatory state might be a shared underlining pathophysiological mechanism.AimsTo investigate the association between anxiety symptoms, CV risks factors and inflammatory markers in an outpatient sample.MethodsCross-sectional study. Inclusion criteria: outpatients aged ≥40 years, attending colonoscopy after positive faecal occult blood test, negative medical history for cancer. Collected data: blood pressure, glycaemia, lipid profile, waist circumference, BMI, PCR (C Reactive Protein), LPS (bacterial Lipopolysaccharide). Psychometric tests: HADS, TCI, IMSA, SF36. Statistical analysis performed with STATA13.ResultsFifty four patients enrolled (27 males, 27 females). Sixteen patients (30.19%) were positive for anxiety symptoms. Thirty-three patients (61.11%) had hypertension, 14 (25.93%) hyperglycaemia and 64.81% were overweight, with frank obesity (BMI≥ 30) in 11 subjects (20.37%). Anxiety symptoms were associated with low hematic HDL values (OR = 0.01; P = 0.01) and high concentration of triglycerides (OR = 0.023; P = 0.02) at the multiple regression model. At the univariate logistic analysis, anxiety was associated with LPS (OR = 1.06; P = 0.04).ConclusionsFurther evidence over the epidemiological link between common mental disorders and CV diseases was collected, with possible hints on pathophysiology and causative mechanisms related to inflammation. The importance of screening for anxiety and depression in medical populations is confirmed. Suggestions on future availability of screening tools based on inflammatory-related indicators should be the focus of future research.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Early cardiac changes induced by a hypercaloric Western-type diet in "subclinical" obesity.

"Obesity cardiomyopathy" effects have been widely described; however, the specific contribution of metabolic changes and altered adipokine secretion are still uncharacterized. Moreover, a diagnosis based on body mass index might not be the most accurate to identify increased adiposity and its outcomes. In this study, we aimed to determine the impact of a Western-type diet [hypercaloric diet (HCD)] ingestion on biventricular structure and function, as well as the metabolic and endocrine changes that occur before the establishment of overt obesity. Wistar rats were fed for 6 wk with a regular diet or HCD. At the end of the protocol, metabolic tests, cardiac structure, and functional evaluation were performed, and blood and tissue samples collected to perform histological, molecular biology, and functional studies. The animals that ingested the HCD presented increased adiposity and larger adipocyte cross-sectional area, but similar body weight compared with the regular diet group. At the cardiac level, HCD induced biventricular cardiomyocyte hypertrophy, fibrosis, increased stiffness, and impaired relaxation. Galectin-3 plasma expression was likewise elevated in the same animals. The nutritional modulation also altered the secretory pattern of the adipose tissue, originating a proinflammatory systemic environment. In this study, we observed that before "clinical" overweight or frank obesity is established, the ingestion of a HCD-induced cardiac remodeling manifests by increased biventricular stiffness and diastolic dysfunction. The mechanism triggering the cardiac alterations appears to be the proinflammatory environment promoted by the adipose tissue dysfunction. Furthermore, galectin-3, a profibrotic molecule, might be a potential biomarker for the myocardial alterations promoted by the HCD before overweight or obesity.

Nutrient-Induced Inflammation in Polycystic Ovary Syndrome: Role in the Development of Metabolic Aberration and Ovarian Dysfunction.

A pathophysiology paradigm shift has emerged with the discovery that polycystic ovary syndrome (PCOS) is a proinflammatory state. Despite the dogma that the compensatory hyperinsulinemia of insulin resistance is the promoter of hyperandrogenism, physiological insulin infusion has no effect on androgen levels in PCOS. The dogma also does not explain the cause of hyperandrogenism and ovarian dysfunction in the 30 to 50% of women with PCOS who are of normal weight and lack insulin resistance. Inflammation is the underpinning of insulin resistance in obesity and type 2 diabetes, and may also be the cause of insulin resistance when present in PCOS. The origin of inflammation in PCOS has been ascribed to excess abdominal adiposity or frank obesity. However, nutrients such as glucose and saturated fat can incite inflammation from circulating mononuclear cells (MNC) of women with PCOS independent of excess adiposity and insulin resistance, and can also promote atherogenesis. Hyperandrogenism activates MNC in the fasting state to increase MNC sensitivity to nutrients, and is a potential mechanism for initiating inflammation in PCOS. However, chronic ovarian androgen suppression does not reduce inflammation in normal-weight women with PCOS. Direct exposure of ovarian theca cells to proinflammatory stimuli in vitro increases androgen production. These findings may be corroborated in vivo with anti-inflammatory therapy to normal-weight insulin-sensitive women with PCOS without abdominal adiposity to observe for amelioration of ovarian dysfunction.

High Carbohydrate Diet with 30% Sucrose Solution: An Optimized Rodent Model for Simulating Human Insulin Resistance

Background: The development of an appropriate animal model that can mimic the actual human disease condition is an important consideration of a successful pharmacological experiment. Methods: To achieve type-2 diabetic conditions similar to that of human, we performed an optimization experiment, taking in to consideration the previously reported methods of inducing type-2 diabetes such as high fat diet, high sucrose diet and high calorie diet models with low dose Streptozotocin (STZ). We adopted High Carbohydrate Diet (HCD) model with some modifications. Post weaned male albino rats were chosen for the experiment and were fed HCD for six months prior to the experiment. The rats were later grouped, treated with sucrose and fructose solutions and STZ was administered at two different doses. The animals were subjected to OGTT. Plasma glucose, insulin, total cholesterol, triglycerides, AST, ALT levels were measured. The comparison was done with both normal pellet diet and HCD rats. Results: The findings demonstrated that HCD induced frank obesity with increased circulating TG levels. The low dose STZ treatment was not encouraging as significant mortality was observed with 35 mg kg-1 STZ and reversal to normoglycemia was observed with 20 mg kg-1 STZ. Conclusion: The group with sucrose supplementation simulated the conditions desirable to mimic human insulin resistance syndrome.

The Relationship between Heart Rate Variability and Adiposity Differs for Central and Overall Adiposity

While frank obesity is associated with reduced HRV, indicative of poorer autonomic nervous system (ANS) function, the association between body mass index (BMI) and HRV is less clear. We hypothesized that effects of adiposity on ANS are mostly mediated by visceral fat and less by subcutaneous fat; therefore, centrally distributed adipose tissue, that is, waist circumference (WC), should be more strongly associated with HRV than overall adiposity (BMI). To examine this hypothesis, we used data collected in a subset of the Baltimore Longitudinal Study of Aging to compare strength of association between HRV and WC to that of HRV and BMI. Time domain HRV variables SDNN (standard deviation of successive differences in normal-to-normal (N-N) intervals) and RMSSD (root mean square of successive differences in N-N intervals) were calculated from 24-hour Holter recordings in 159 participants (29–96 years). Increasing WC was associated with decreasing SDNN and RMSSD in younger but not older participants (P value for WC-by-age interaction = 0.003). BMI was not associated with either SDNN or RMSSD at any age. In conclusion, central adiposity may contribute to sympathetic and parasympathetic ANS declines early in life.

Intestinal Mucosal Triacylglycerol Accumulation Secondary to Decreased Lipid Secretion in Obese and High Fat Fed Mice

The ectopic deposition of fat in liver and muscle during obesity is well established, however surprisingly little is known about the intestine. We used the ob/ob mouse and C57BL6/J mice fed a high fat (HF) diet to examine the effects of obesity and the effects of HF feeding, respectively, on intestinal mucosal triacylglycerol (TG) accumulation. Male C57BL6/J (wild-type, WT) mice were fed low fat (LF; 10% kcal as fat) or HF (45%) diets, and ob/ob mice were fed the LF diet, for 3 weeks. In this time frame, the WT–HF mice did not become obese, enabling independent examination of effects of the HF diet and effects of obesity. Analysis of intestinal lipid extracts from fed and fasted animals demonstrated that the mucosa, like other tissues, accumulates excess lipid. In the fed state, mucosal triacylglycerol (TG) levels were threefold and fivefold higher in the WT–HF and ob/ob mice, respectively, relative to the WT–LF mice. In the fasted state, mucosa from ob/ob mice had threefold higher TG levels relative to WT–LF mucosa. q-PCR analysis of mucosal mRNA from fed state mice showed alterations in the expression of several genes related to both anabolic and catabolic lipid metabolism pathways in WT–HF and ob/ob mice relative to WT–LF controls. Fewer changes were found in mucosal samples from the fasted state animals. Remarkably, oral fat tolerance tests showed a striking reduction in the plasma appearance of an oral fat load in the ob/ob and WT–HF mice compared to WT–LF. Overall, the results demonstrate that the intestinal mucosa accumulates excess TG during obesity. Changes in the expression of lipid metabolic and transport genes, as well as reduced secretion of dietary lipid from the mucosal cells into the circulation, may contribute to the TG accumulation in intestinal mucosa during obesity. Moreover, even in the absence of frank obesity, HF feeding leads to a large decrease in the rate of intestinal lipid secretion.

Nonalcoholic Fatty Liver Disease in South Asia.

ABSTRACTNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the West, and is also increasing alarmingly in South Asia, reaching an epidemic proportion of 30% because of epidemic of obesity and metabolic syndrome (MS) in younger South Asians in the last two decades. Prevalence of MS and fatty liver is escalating in geometric progression in South Asian countries, such as India, Pakistan, Sri Lanka, Bangladesh, Nepal, Bhutan, Burma, and Maldives because of sedentary lifestyle, poor health awareness, socioeconomic growth, affluence, urbanization, and dietary westernization. Almost 20% of world’s population resides in South Asia, making it the most populous and most densely populated geographic region in the world, thereby having most of MS and NAFLD cases within its territory. The risk factors and course of NAFLD do not differ between South Asians and other ethnic populations, but the obesity epidemic is more recent in South Asia than elsewhere in the world. Nonalcoholic fatty liver disease may progress through stages of simple bland steatosis, nonalcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). It is frequently associated with obesity, MS, dyslipidemia, insulin resistance (IR), and type-2 diabetes mellitus (DM). Nonalcoholic fatty liver disease is frequently diagnosed with abdominal ultrasonography (US) study. Despite its high prevalence in the community till now, no definitive pharmacotherapy is available for NAFLD. However, modification of risk factors, such as dyslipidemia, control of diabetes, and weight reduction do help to some extent. The nonobese South Asians are also at increased risk of having NAFLD and NASH as, despite of absence of frank obesity in South Asians, they are metabolically more obese compared to other ethnic population and more prone to develop NAFLD-related complications. Therefore, the cost-effective US abdomen should be included in the list of tests for persons undergoing preemployment or master health checkups for early diagnosis of NAFLD in this resource-constraint South Asian region, so that early necessary measures can be undertaken to reduce NAFLD associated morbidity and mortality in the community.How to cite this articlePati GK, Singh SP. Nonalcoholic Fatty Liver Disease in South Asia. Euroasian J Hepato-Gastroenterol 2016;6(2):154-162.

Early Indicators of the Dysmetabolic Syndrome in Young Survivors of Acute Lymphoblastic Leukemia in Childhood.

An increased incidence of obesity and cardiovascular morbidity and mortality was recently observed in adult survivors of childhood malignancies younger than 45 years. The purpose of this study was to investigate the presence of early indicators of the dysmetabolic syndrome in a population of young survivors of acute lymphoblastic leukemia (ALL) in childhood.Patients and methods: Our study included 58 patients (31 males), aged 5–24 years (mean 12.9 years) with ALL, who had finished their treatment by the same protocol at least 2 years before the study (mean 5.1 years, range 2–10 years). Ten patients had received cranial irradiation (18 Gy). No patient had a history of thyroid disease or diabetes mellitus or received hormonal substitution. We obtained a detailed history of their diet habits and level of physical activity and measured their body mass index (BMI) and blood pressure (BP). Complete blood counts and blood chemistry tests were also obtained. Finally, bone density was measured in the lumbar spine and femur with DEXA.Results: Diet enriched in lipids and low carbohydrates was reported by 43/58 (74%), while absence of any athletic activity by 38/58 (65%) of the patients. Frank obesity with a BMI >30 or its equivalent for age and gender was observed in 12/58 (21%) of the patients, while 25/58 (43%) were overweight, with a BMI >25<30 or its equivalent for age and gender.1 Increased systolic and/or diastolic BP (>95th percentile) was observed in 13/58 patients (22%), while in 25/58 (43%) it was > the 75th percentile. Dyslipidemia characterized by one, two, or three indices (serum cholesterol, triglycerides or LDL concentrations >95th percentile) was respectively detected in 20/58 (35%), 13/58 (22%), and 7/58 (12%) of the patients. Reduced serum HDL concentrations (<5th percentile) was observed in 12/58 (21%) of the patients. Slightly elevated free fatty acids were detected in 11/58 (19%) and hepatic enzymes in 7/58 (12%) of the patients. Increased fasting insulin was seen in 14/58 (24%) of the patients and HbA1c in 11/58 (19%) of them, however, fasting blood glucose was normal in all patients. Finally, increased inflammatory indices, namely C-reactive protein (CRP) or serum amyloid A (SAA), were detected in 9/58 patients (15%), reduced IGF-1 in 9/58 (15%) and thyroid hormone abnormalities in 5/58 (9%). All the patients with thyroid dysfunction, however, had received cranial irradiation. Osteopenia [Ζ score matched for age and gender of T score bone density: -(1–2.5) SD] was detected in 41/58 (71%) of the patients. None had frank osteoporosis.Conclusion: Survivors of childhood ALL have early indicators of high risk for the dysmetabolic syndrome. Modification of diet, body weight control, stress reduction, and reinforcement of an exercise program will hopefully be helpful in preventing the cardiovascular sequelae of the syndrome, improve the quality of life and enhance the life expectancy in this group of patients.

Rimonabant: Unique and Promising

The global pandemic of overweight has evoked increasing alarm as a risk factor for multiple adverse health outcomes. Prominent among these are obesity, metabolic syndrome, and diabetes, all of which promote the development of cardiovascular disease. The magnitude of the problem is reflected by estimates that on a worldwide scale, overweight (body mass index >25 kg/m2) and frank obesity (body mass index >30 kg/m2) affect 1 billion and 300,000 persons, respectively,1 and in this country 97 million people are categorized as overweight or obese.2 This situation prompted The Surgeon Generals' Call to Action to Prevent and Decrease Overweight and Obesity.3 It is well known that overnutrition and underactivity play important roles in the development of obesity. Together with the persistence of cigarette smoking, these unfavorable lifestyles are prime examples of the extent to which adverse health outcomes are a result of self-imposed practices. Although it has been established that favorable lifestyle modifications exert beneficial effects on obesity and its clinical aftermaths, alteration of personal habits has proved a daunting challenge to individuals, health care providers, and society. In such circumstances, the search for pharmacologic alleviation has been our practice, often with gratifying results, as exemplified by the statin class of drugs.4 Enter rimonabant—a unique drug with therapeutic potential in obesity, smoking, and the metabolic syndrome. Rimonabant is the first of a new class of drugs that acts as a selective inhibitor of cannabinoid-1 receptors in the endocannabinoid system. Stimulation of these receptors, which are densest in the brain, appears to influence 1) lipid and glucose metabolism in adipose tissue; and 2) regulation of appetite, energy balance, and nicotine dependence.5 Through these mechanisms, the endocannabinoid system appears to be involved in weight gain and the urge to smoke. Rimonabant has a high affinity for central cannabinoid receptors, blocks the actions of cannabinoid receptor agonists, and has induced weight loss in animal investigations. Evidence that the drug can induce decreased appetite and weight loss has been extended to humans in phase 1 and 2 trials, which have led to the current phase 3 prospective, randomized, placebo-controlled trials on obesity and smoking cessation. The phase 3 trials on obesity (Rimonabant in Obesity) include RIO-Lipids, RIO-Diabetes, RIO-Europe, and RIO-America. Preliminary results have shown favorable effects of rimonabant compared with placebo on weight loss, multiple factors of the metabolic syndrome, and incidence of the metabolic syndrome.6 The effect of the drug is dose-related, and approximately 60% of study patients have lost 5%-10% of body weight. The results in the metabolic syndrome are unique in that there is currently no single drug aimed at the cluster of factors comprising this condition. RIO-Europe was recently published and confirmed the preliminary findings.7 The effects of rimonabant on smoking cessation are currently being investigated in the three STRATUS trials (Studies with Rimonabant and Tobacco Use). Initial findings suggest a significantly higher quit rate compared with placebo. Adverse effects of rimonabant have been dose-related and generally mild, including gastrointestinal disturbances, nausea, dizziness, and upper respiratory tract infections.7 These promising results suggest that rimonabant may afford a unique approach to combating two of the major health hazards of our society: obesity and smoking. Multiple, long-term studies are in progress to determine whether the early promise will translate into enduring fulfillment.

Confronting the Epidemic of Childhood Obesity

In a recent policy statement emphasizing early identification and prevention strategies, the American Academy of Pediatrics Committee on Nutrition refers to an “epidemic” of excessive weight and frank obesity in children.1 Similarly, this rather graphic term can be found in a number of recent articles, commentaries, reports from expert consensus conferences, and pronouncements by public officials. “Epidemic” is usually used to describe the spread of an infectious disease. Although not contagious, childhood obesity is spreading like influenza, and we have no vaccine against it. Its prevalence is increasing worldwide, even in less-developed countries. In the United States, childhood obesity is the most common nutritional disorder (1 in 3 are overweight or close to it), with disproportionately high rates in ethnic minorities. American children are on … Address correspondence to Myron Genel, MD, Department of Pediatrics, Yale University School of Medicine, PO Box 208081, New Haven, CT 06520-8081. E-mail: myron.genel{at}yale.edu

Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat.

To characterize the developmental changes in adipose and muscle lipoprotein lipase (LPL) activity in the atherosclerosis-prone JCR:LA-corpulent rat, and to test the hypothesis that tissue-specific abnormalities in LPL activity precede the establishment of obesity. Lean (+/?) and obese cp/cp male JCR:LA rats were studied at 4, 5 and 8 weeks of age, that is at the onset of obesity, and at a time when obesity is well established. Assessment was made of plasma variables related to glucose and lipid metabolism and of LPL activity in several adipose depots, skeletal muscles and the heart. At week 4, body weights were identical in both genotypes and began to diverge at week 5. Eight-week-old cp/cp rats weighed 35% more than their lean counterparts. Perirenal and epididymal adipose depot weights were also identical in both genotypes at week 4 and began to increase in cp/cp rats at week 5, whereas the subcutaneous depot of 4-week-old cp/cp rats was slightly enlarged. At week 4, the cp/cp rats were hyperinsulinemic (5-fold), hyperleptinemic (30-fold) and hypertriglyceridemic (3-fold) compared to their lean counterparts, and their liver contained twice as much triglyceride. The 4-week-old cp/cp rats displayed 2-7-fold higher LPL specific activity in the various adipose depots compared to lean rats, and enzyme activity remained higher in obese than in lean rats at all subsequent ages. In contrast, LPL activity in the vastus lateralis, gastrocnemius and heart muscles of 4-week-old obese rats was approximately half that observed in lean animals. Profound, persistent alterations in the tissue-specific modulation of LPL activity are established in the JCR:LA cp/cp rat prior to the development of frank obesity. The increase in adipose tissue LPL activity and its decrease in muscle tissues are likely to be related to the concomitant alterations in insulinemia and triglyceridemia, respectively. The pre-obesity, tissue-specific alterations in LPL activity may be considered as an integrated adaptation to increased lipid flux aimed at driving lipids toward storage sites and limiting their uptake by triglyceride-laden muscles.

Secular changes in cardiovascular risk factors over 30 years in Swedish men aged 50: the study of men born in 1913, 1923, 1933 and 1943.

To study secular trends in cardiovascular risk factors in men aged 50 over a period of 30 years. Cross-sectional studies of successive cohorts of men from 1963 to 1993. City of Göteborg, Sweden. Four random population samples of men born in 1913, 1923, 1933 and 1943, aged 50 when they were examined in 1963, 1973, 1983, and 1993 (n = 855, 226, 776, and 798, respectively). Anthropometric measurements, blood pressure, serum cholesterol and triglycerides and smoking habits over three decades. Over 30 years, men increased in weight from a mean (SD) of 75.9 (11.0) kg to 82.8 (12.1) kg and gained 3.4 cm in height, with a net increase in body mass index from 24.8 (3.2) to 26.0 (3.4) kg m-2 (P < 0.0001), and a concomitant increase in waist circumference. The proportion of men who were overweight but not obese (BMI = 25-30 kg m-2) increased from 38 to 47%, whereas the prevalence of frank obesity (more than 30 kg m-2) increased from 6% in 1963 to 11% in 1993. Despite the increase in weight, mean systolic blood pressure fell by almost 10 mmHg (P < 0.0001). Mean serum cholesterol concentration decreased from 6.42 (1.12) to 5.88 (1.04) (P < 0.0001). Serum triglycerides increased from 1.26 (0.77) to 1.69 (1.04) mmol L-1 (P = 0.001). The proportion of men who smoked decreased from 56% in 1963 to 30% in 1993 (P < 0.0001). This was due more to an increase in smoking cessation rates than to an increase in the proportion of men who had never smoked. In particular, smokers and former smokers are now more obese than the corresponding categories 30 years ago and smokers are no longer leaner than men who have never smoked. Over a period of 30 years, serum cholesterol as well as systolic blood pressure and the prevalence of smoking decreased. This favourable decline in coronary risk factors was offset by an appreciable increase in body mass index and waist circumference.

Insulin resistance, polycystic ovary syndrome and metformin.

Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.

Body size and fatness of free-living baboons reflect food availability and activity levels.

We used morphometric techniques and isotope-labeled water to investigate the influence of abundant, accessible food and resultant low activity levels on body size and fatness in free-living adolescent and adult baboons as compared to animals in the same population that experienced more typical, wild-feeding conditions. Females that had access to abundant food from a nearby garbage dump averaged 16.7 kg body mass, 50% more than their wild-feeding counterparts in adjacent home ranges. Little of the difference was due to lean mass: the animals with an accessible abundance of food averaged 23.2% body fat in contrast to 1.9% for the wild-feeding animals. Significant differences between feeding conditions were found for all measured skinfolds and for upper arm circumference but not for linear measurements. Differences between feeding conditions were less for males than for females, perhaps reflecting persistent effects of nutritional conditions during the first eight years of life before dispersal from the group of birth. The difference in fatness between feeding conditions was similar to the difference between humans with frank obesity and those that are considered lean, but in both cases the percentages of body fat in the baboons were considerably less than those observed in humans. In levels of fatness, the relatively sedentary animals resembled their counterparts in group-housed captive conditions. © 1993 Wiley-Liss, Inc.