Comparison of the obesity phenotypes related to monosodium glutamate effect on arcuate nucleus and/or the high fat diet feeding in C57BL/6 and NMRI mice

In this study, susceptibility of inbred C57BL/6 and outbred NMRI mice to monosodium glutamate (MSG) obesity or diet-induced obesity (DIO) was compared in terms of food intake, body weight, adiposity as well as leptin, insulin and glucose levels. MSG obesity is an early-onset obesity resulting from MSG-induced lesions in arcuate nucleus to neonatal mice. Both male and female C57BL/6 and NMRI mice with MSG obesity did not differ in body weight from their lean controls, but had dramatically increased fat to body weight ratio. All MSG obese mice developed severe hyperleptinemia, more remarkable in females, but only NMRI male mice showed massive hyperinsulinemia and an extremely high HOMA index that pointed to development of insulin resistance. Diet-induced obesity is a late-onset obesity; it developed during 16-week-long feeding with high-fat diet containing 60 % calories as fat. Inbred C57BL/6 mice, which are frequently used in DIO studies, both male and female, had significantly increased fat to body weight ratio and leptin and glucose levels compared with their appropriate lean controls, but only female C57BL/6 mice had also significantly elevated body weight and insulin level. NMRI mice were less prone to DIO than C57BL/6 ones and did not show significant changes in metabolic parameters after feeding with high-fat diet.     

Characterization of β‐Cell Mass and Insulin Resistance in Diet‐induced Obese and Diet‐resistant Rats

The selectively bred diet‐induced obese (DIO) and diet‐resistant (DR) rats represent a polygenetic animal model mimicking most clinical variables characterizing the human metabolic syndrome. When fed a high‐energy (HE) diet DIO rats develop visceral obesity, dyslipidemia, hyperinsulinemia, and insulin resistance but never frank diabetes. To improve our understanding of the underlying cause for the deteriorating glucose and insulin parameters, we have investigated possible adaptive responses in DIO and DR rats at the level of the insulin‐producing β‐cells. At the time of weaning, DR rats were found to have a higher body weight and β‐cell mass compared to DIO rats, and elevated insulin and glucose responses to an oral glucose load. However, at 2.5 months of age, and for the remaining study period, the effect of genotype became evident: the chow‐fed DIO rats steadily increased their body weight and β‐cell mass, as well as insulin and glucose levels compared to the DR rats. HE feeding affected both DIO and DR rats leading to an increased body weight and an increased β‐cell mass. Interestingly, although the β‐cell mass in DR rats and chow‐fed DIO rats appeared to constantly increase with age, the β‐cell mass in the HE‐fed DIO rats did not continue to do so. This might constitute part of an explanation for their reduced glucose tolerance. Collectively, the data support the use of HE‐fed DIO rats as a model of human obesity and insulin resistance, and accentuate its relevance for studies examining the benefit of pharmaceutical compounds targeting this disease complex.     

Effects of Pravastatin on Obesity,Diabetes, and Adiponectin in Diet‐induced Obese Mice

Objective: The aim of this study was to investigate the in vivo effects of pravastatin on the development of obesity and diabetes in diet‐induced obese (DIO) mice. Methods and Procedures: We examined food intake, body‐weight changes, visceral white adipose tissue (WAT) adiponectin and resistin levels, and energy metabolism. Results: Treatment with 100 mg/kg/day pravastatin for 28 days decreased diet‐induced weight gain and visceral adiposity. In addition, the weight of the WAT, the triglyceride (TG) contents of the liver and muscles, and the levels of serum insulin improved in the pravastatin‐treated DIO mice. Furthermore, pravastatin treatment changed the WAT adiponectin and resistin mRNA expression and serum levels compared with the controls. Finally, pravastatin treatment increased oxygen consumption and decreased the respiratory quotient (RQ). Discussion: Pravastatin treatment prevents the development of obesity and diabetes in DIO mice. The prevention of obesity may be mediated by increased oxygen consumption and a decrease in the RQ. These results provide novel insights into the use of pravastatin as a therapeutic tool for metabolic syndromes.     

Low Resting and Sleeping Energy Expenditure and Fat Use Do Not Contribute to Obesity in Women

Objective: Determine whether sleeping and resting energy expenditure and sleeping, resting, and 24‐hour fuel use distinguish obesity‐prone from obesity‐resistant women and whether these metabolic factors explain long‐term weight gain. Research Methods and Procedures: Forty‐nine previously overweight but currently normal‐weight women were compared with 49 never‐overweight controls. To date, 87% of the 98 women have been re‐evaluated after 1 year of follow‐up, without intervention, and 38% after 2 years. Subjects were studied at a General Clinical Research Center after 4 weeks of tightly controlled conditions of energy balance and macronutrient intake. Forty‐nine obesity‐prone weight‐reduced women were group‐matched with 49 never‐overweight obesity‐resistant controls. All were premenopausal, sedentary, and normoglycemic. Energy expenditure and fuel use were assessed using chamber calorimetry. Body composition was assessed using DXA. Results: At baseline, percent body fat was not different between the obesity‐prone and control women (33 ± 4% vs. 32 ± 5%, respectively; p = 0.22). Analysis of covariance results show that after adjusting for lean and fat mass, sleeping and resting energy expenditure of obesity‐prone women was within 2% of controls. Neither sleeping nor resting energy expenditure nor sleeping, resting, or 24‐hour fuel use was significantly different between the groups (p > 0.25). None of the metabolic variables contributed significantly to patterns of weight gain at 1 or 2 years of follow‐up. Discussion: The results suggest that when resting and sleeping energy expenditure and fuel use are assessed under tightly controlled conditions, these metabolic factors do not distinguish obesity‐prone from obesity‐resistant women or explain long‐term weight changes.     

Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance

Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase Cepsilon was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappaB activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.     

Adipokine and insulin profiles distinguish diabetogenic and non-diabetogenic obesities in mice

Objective: To use longitudinal profiling of plasma adipokines to distinguish diabetogenic vs. non‐diabetogenic obesity syndrome in two new mouse models of polygenic obesity. Research Methods and Procedures: Male mice of the NONcNZO5 strain develop a polygenic obesity syndrome uncomplicated by diabetes, whereas NONcNZO10 males develop a comparable polygenic obesity that precipitates type 2 diabetes. A multiplex immunoassay for simultaneous measurement of insulin and a panel of mouse adipokines (leptin, resistin, adiponectin, interleukin‐6, tumor necrosis factor α, macrophage chemoattractant protein‐1, plasminogen activator inhibitor‐1) were used to profile longitudinal changes in these strains between 4 and 16 weeks of age that might distinguish the non‐diabetogenic vs. diabetogenic obesity (diabesity). Results: Both strains became adipose, with NONcNZO5 males attaining a higher mean body weight with a higher percentage fat content. Weight gain in NONcNZO5 was accompanied by a transient peak in plasma insulin (PI) at 8 weeks followed by a decline into normal range, with normoglycemia maintained throughout. In contrast, NONcNZO10 showed no early PI secretory response because both body weight and plasma glucose increased between 4 and 8 weeks. Only after 12 weeks, with hyperglycemia established, was a delayed PI secretory response observed. Neither plasma leptin nor adiponectin concentrations significantly differentiated the two syndromes over time. However, repeated measures ANOVA showed that NONcNZO10 males maintained significantly higher plasma concentrations of two adipokines, resistin and plasminogen activator inhibitor‐1, and the pro‐inflammatory cytokine/adipokine macrophage chemoattractant protein‐1. Discussion: Longitudinal profiling of PI and adipokines in two new mouse models developing moderate obesity demonstrated that specific marker signatures differentiated a non‐diabetogenic obesity from a diabetogenic obesity.     

Dosing Common Medications in Hospitalized Pediatric Patients with Obesity: A Review

Medication management in children and adolescents with obesity is challenging because both developmental and pathophysiological changes may impact drug disposition and response. Evidence to date indicates an effect of obesity on drug disposition for certain drugs used in this population. This work identified published studies evaluating drug dosing, pharmacokinetics (PK), and effect in pediatric patients with obesity, focusing on 70 common medications used in a pediatric network of 42 US medical centers. A PubMed search revealed 33 studies providing PK and/or effectiveness data for 23% (16 of 70) of medications, 44% of which have just one study and can be considered exploratory. This work appraising 4 decades of literature shows several promising approaches: greater use of PK models applied to prospective clinical studies, dosing recommendations derived from both PK and safety, and multiyear effectiveness data on drugs for chronic conditions (e.g., asthma). Most studies make dose recommendations but are weakened by retrospective study design, small study populations, and no controls or historic controls. Dosing decisions continue to rely on extrapolating knowledge, including targeting systemic drug exposure typically achieved in adults. Optimal weight‐based dosing strategies vary by drug and warrant prospective, controlled studies incorporating PK and modeling and simulation to complement clinical assessment.     

11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue and prospective changes in body weight and insulin resistance

Objective: Increased mRNA and activity levels of 11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1) in human adipose tissue (AT) are associated with obesity and insulin resistance. The aim of our study was to investigate whether 11βHSD1 expression or activity in abdominal subcutaneous AT of non‐diabetic subjects are associated with subsequent changes in body weight and insulin resistance [homeostasis model assessment of insulin resistance (HOMA‐IR)]. Research Methods and Procedures: Prospective analyses were performed in 20 subjects (two whites and 18 Pima Indians) who had baseline measurements of 11βHSD1 mRNA and activity in whole AT (follow‐up, 0.3 to 4.9 years) and in 47 Pima Indians who had baseline assessments of 11βHSD1 mRNA in isolated adipocytes (follow‐up, 0.8 to 5.3 years). Results: In whole AT, although 11βHSD1 mRNA levels showed positive associations with changes in weight and HOMA‐IR, 11βHSD1 activity was associated with changes in HOMA‐IR but not in body weight. 11βHSD1 mRNA levels in isolated adipocytes were not associated with follow‐up changes in any of the anthropometric or metabolic variables. Discussion: Our results indicate that increased expression of 11βHSD1 in subcutaneous abdominal AT may contribute to risk of worsening obesity and insulin resistance. This prospective relationship does not seem to be mediated by increased 11βHSD1 expression in adipocytes.     

Food Intake‐independent Effects of CB1 Antagonism on Glucose and Lipid Metabolism

Overactivity of the endocannabinoid system (ECS) has been linked to abdominal obesity and other risk factors for cardiovascular disease and type 2 diabetes. Conversely, administration of cannabinoid receptor type 1 (CB1) antagonists reduces adiposity in obese animals and humans. This effect is only in part secondary to the anorectic action of CB1 agonists. In order to assess the actions of CB1 antagonism on glucose homeostasis, diet‐induced obese (DIO) rats received the CB1 antagonist rimonabant (10 mg/kg, intraperitoneally (IP)) or its vehicle for 4 weeks, or were pair‐fed to the rimonabant‐treated group for the same length of time. Rimonabant treatment transiently reduced food intake, while inducing body weight loss throughout the study. Rats receiving rimonabant had significantly less body fat and circulating leptin compared to both vehicle and pair‐fed groups. Rimonabant, but not pair‐feeding, also significantly decreased circulating nonesterified fatty acid (NEFA) and triacylglycerol (TG) levels, and reduced TG content in oxidative skeletal muscle. Although no effects were observed during a glucose tolerance test (GTT), rimonabant restored insulin sensitivity to that of chow‐fed, lean controls during an insulin tolerance test (ITT). Conversely, a single dose of rimonabant to DIO rats had no acute effect on insulin sensitivity. These findings suggest that in diet‐induced obesity, chronic CB1 antagonism causes weight loss and improves insulin sensitivity by diverting lipids from storage toward utilization. These effects are independent of the anorectic action of the drug.     

Insulin Resistance and Oxidative Stress Influence Colony‐Forming Unit‐Endothelial Cells Capacity in Obese Patients

The aim of this study was to investigate the relationship between a sub‐population of endothelial progenitor cells (EPC), namely colony‐forming unit‐endothelial cells (CFU‐EC), their colony‐forming capacity and variable clinical parameters, including insulin resistance and oxidative stress, in obese individuals. Thirty‐eight obese adults (aged 42.5 ± 12.7), with BMI 32.3 ± 4.0 and 13 normal‐weight controls (aged 48.2 ± 12.9; BMI 23.2 ± 2.3) were studied. CFU‐EC colony‐forming capacity was impaired in the group of obese individuals compared to the normal‐weight controls (P = 0.001). The inverse correlation between homeostasis model assessment‐insulin resistance (HOMA_IR) index and CFU‐EC number (r = ?0.558, P < 0.0001) as well as positive total antioxidant status of plasma (TAS)/CFU‐EC relation were noticed during the study. Additionally, correlations between the concentration of triglycerides (TG), high‐density lipoproteins (HDLs), and body composition parameters in the obese participants were established. Our results demonstrate that insulin resistance and oxidative stress have a significant impact on the CFU‐EC colony formation in obesity. Moreover, in multivariate regression analysis, in both studied groups, the HOMA_IR index and HDL concentration were independent predictors of the number of CFU‐EC. Endothelium dysfunction, which can be present in obesity, may in part be caused by EPC function impairment in this condition.     

Lipoprotein alterations, abdominal fat distribution and breast cancer.

Plasma lipid profile and abdominal obesity have been associated with breast cancer risk, however published results have been inconsistent. To clarify these associations we studied lipid and lipoprotein alterations, obesity degree and body fat distribution, in 30 newly diagnosed breast cancer patients without treatment and 30 controls matched by age and menopausal status. Both pre and postmenopausal breast cancer patients presented higher body mass index, waist/hip ratio and insulin levels than their matched controls. An increase in triglycerides and a decrease in HDL-cholesterol, especially in the HDL2 subfraction, were observed in patients with breast cancer. Besides, HDL particle from these patients showed increased apo A1/HDL-cholesterol ratio. These alterations were correlated with waist/hip ratio. The association between lipoprotein alterations and abdominal obesity independent of menopausal status, in untreated newly diagnosed breast cancer patients is reported for the first time in this study.     

Inhibition of PTP1B by Trodusquemine (MSI‐1436) Causes Fat‐specific Weight Loss in Diet‐induced Obese Mice

Trodusquemine (MSI‐1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of trodusquemine in the clinic, we investigated the effects of trodusquemine treatment in a murine model of diet‐induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat‐specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that trodusquemine selectively inhibited protein‐tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin‐stimulated tyrosine phosphorylation of insulin receptor (IR) β and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat‐specific weight loss and improve insulin and leptin levels.     

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s) of adipose-PTP1B-deficiency on body mass and insulin resistance. To definitively establish the role of adipocyte-PTP1B in body mass regulation and glucose homeostasis, adipocyte-specific-PTP1B knockout mice (adip-crePTP1B(-/-)) were generated using the adiponectin-promoter to drive Cre-recombinase expression. Chow-fed adip-crePTP1B(-/-) mice display enlarged adipocytes, despite having similar body weight/adiposity and glucose homeostasis compared to controls. High-fat diet (HFD)-fed adip-crePTP1B(-/-) mice display no differences in body weight/adiposity but exhibit larger adipocytes, increased circulating glucose and leptin levels, reduced leptin sensitivity and increased basal lipogenesis compared to controls. This is associated with decreased insulin receptor (IR) and Akt/PKB phosphorylation, increased lipogenic gene expression and increased hypoxia-induced factor-1-alpha (Hif-1α) expression. Adipocyte-specific PTP1B deletion does not beneficially manipulate signaling pathways regulating glucose homeostasis, lipid metabolism or adipokine secretion in adipocytes. Moreover, PTP1B does not appear to be the major negative regulator of the IR in adipocytes.     

An Endoluminal Sleeve Induces Substantial Weight Loss and Normalizes Glucose Homeostasis in Rats with Diet‐Induced Obesity

To investigate the contributions of two surgical gut manipulations—exclusion of the proximal intestine from alimentary flow and exposure of the jejunum to partially digested nutrients—to body weight regulation and metabolism, we have developed a rat model of an investigational device, the endoluminal sleeve (ELS). The ELS is a 10 cm, nutrient‐impermeable, flexible tube designed for endoluminal implantation. ELS devices were surgically implanted in the duodenal bulb of rats with diet‐induced obesity. Body weight, food intake, stool caloric content, and glucose homeostasis were subsequently evaluated. ELS‐implanted rats demonstrated a 20% reduction of body weight compared to sham‐operated (SO) controls. ELS‐treated animals consumed an average of 27% fewer kcal/day than SO, and there was no evidence of malabsorption. ELS treatment improved fasting glycemia and glucose tolerance after oral and intraperitoneal (IP) administration. ELS treatment enhanced insulin sensitivity, as demonstrated by decreased fasting and glucose‐stimulated insulin levels and confirmed by calculation of homeostasis model assessment of insulin resistance (IR). These data suggest that selective bypass of the proximal intestine by ELS, with enhanced delivery of partially digested nutrients to the jejunum, mimics many of the effects of Roux‐en‐Y gastric bypass (RYGB) on body weight and glucose metabolism. Thus, ELS implantation may be an effective treatment for obesity and diabetes. Since the ELS device is amenable to endoscopic placement, it may offer a valuable alternative to more invasive surgical approaches in selected patients with obesity and its metabolic complications.     

Differential secretion of satiety hormones with progression of obesity in JCR:LA-corpulent rats

Objective: To characterize the gastrointestinal tract at the onset and in well‐established obesity. Methods and Procedures: Lean (+/?) and obese (cp/cp) male JCR:LA‐cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified. Results: At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well‐established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide‐1 (GLP‐1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats. Discussion: Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.     

Biochemical and Anthropometric Characterization of Morbid Obesity in a Large Utah Pedigree

A Utah family with morbid obesity was extended to include 122 persons in four generations for the purpose of characterizing anthropometric and biochemical variables in family members with and without morbid obesity. Seventy-seven subjects had blood drawn for biochemical analyses. Of the 77 subjects, 12 were morbidly obese (≥44.5 kg or 100 pounds overweight), 20 were between 22.5–45.4 kg (50 and 99 pounds) overweight and 45 were less than 22.5 kg (50 pounds) overweight Sixty-two randomly-ascertained controls were used for comparisons of age- and gender-adjusted study variables. Morbidly obese subjects had mean body mass indices (BMI) of 41.0 kg/m² (62 kg over ideal weight) compared to 25.3 kg/m² (10 kg overweight) in the <22.5 kg family members (p<0.001). The <22.5 kg family members had lower BMI than the random controls (27.6 kg/m², p<0.05), indicating clear bimodality of obesity within the pedigree. Percent body fat from bioelectrical impedance was 35% versus 24% in the morbidly obese and the <22.5 kg subjects, respectively. Ideal body weight was similar among the three pedigree weight groups. Hip and waist circumferences were much larger in the morbidly obese and the waist-to-hip ratio remained significantly greater in the morbidly obese subjects compared to the <22.5 kg group. Morbidly obese subjects had elevated triglycerides and VLDL-C levels, low HDL-levels, and normal LDL-C levels. Fasting insulin was the best predictor of morbid obesity of all biochemical and lipid measurements (odds ratio of 4.5). Fasting insulin levels and the insulin-to-glucose ratio were more than twice as high as control levels. Even after adjusting for differences in BMI, fasting insulin and the insulin to glucose ratio were elevated in the morbidly obese subjects indicating that insulin levels were inappropriately high for their weight compared to this relationship found in the other groups. Adjusted insulin levels for the 22.5–45.4 kg group were similar to controls, indicating insulin level was at the predicted level for their weight. In conclusion, individuals with morbid obesity appeared to have greater insulin resistance than could be explained by their weight. CHD risk from elevated LD L-C was not present, but CHD risk was increased by the so-called multiple metabolic syndrome (insulin resistance, high triglycerides and low HDL-C).