GQ-16, a Novel Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) Ligand, Promotes Insulin Sensitization without Weight Gain

The recent discovery that peroxisome proliferator-activated receptor gamma (PPAR gamma) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPAR gamma activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPAR gamma. The structure of GQ-16 bound to PPAR gamma demonstrates that the compound utilizes a binding mode distinct from other reported PPAR gamma ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the beta-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPAR gamma-based therapeutics stabilize the beta-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPAR gamma modulators that retain antidiabetic actions while minimizing untoward effects.

Trabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain

Second generation antipsychotics (SGAs) have been linked to metabolic and bone disorders in clinical studies, but the mechanisms of these side effects remain unclear. Additionally, no studies have examined whether SGAs cause bone loss in mice. Using in vivo and in vitro modeling we examined the effects of risperidone, the most commonly prescribed SGA, on bone in C57BL6/J (B6) mice. Mice were treated with risperidone orally by food supplementation at a dose of 1.25 mg/kg daily for 5 and 8 weeks, starting at 3.5 weeks of age. Risperidone reduced trabecular BV/TV, trabecular number and percent cortical area. Trabecular histomorphometry demonstrated increased resorption parameters, with no change in osteoblast number or function. Risperidone also altered adipose tissue distribution such that white adipose tissue mass was reduced and liver had significantly higher lipid infiltration. Next, in order to tightly control risperidone exposure, we administered risperidone by chronic subcutaneous infusion with osmotic minipumps (0.5 mg/kg daily for 4 weeks) in 7 week old female B6 mice. Similar trabecular and cortical bone differences were observed compared to the orally treated groups (reduced trabecular BV/TV, and connectivity density, and reduced percent cortical area) with no change in body mass, percent body fat, glucose tolerance or insulin sensitivity. Unlike in orally treated mice, risperidone infusion reduced bone formation parameters (serum P1NP, MAR and BFR/BV). Resorption parameters were elevated, but this increase did not reach statistical significance. To determine if risperidone could directly affect bone cells, primary bone marrow cells were cultured with osteoclast or osteoblast differentiation media. Risperidone was added to culture medium in clinically relevant doses of 0, 2.5 or 25 ng/ml. The number of osteoclasts was significantly increased by addition in vitro of risperidone while osteoblast differentiation was not altered. These studies indicate that risperidone treatment can have negative skeletal consequences by direct activation of osteoclast activity and by indirect non-cell autonomous mechanisms. Our findings further support the tenet that the negative side effects of SGAs on bone mass should be considered when weighing potential risks and benefits, especially in children and adolescents who have not yet reached peak bone mass. This article is part of a Special Issue entitled: Interactions Between Bone, Adipose Tissue and Metabolism. (C) 2011 Elsevier Inc. All rights reserved.

Physical training prevents body weight gain but does not modify adipose tissue gene expression

The relationship of body weight (BW) with white adipose tissue (WAT) mass and WAT gene expression pattern was investigated in mice submitted to physical training (PT). Adult male C57BL/6 mice were submitted to two 1.5-h daily swimming sessions (T, N = 18), 5 days/week for 4 weeks or maintained sedentary (S, N = 15). Citrate synthase activity increased significantly in the T group (P < 0.05). S mice had a substantial weight gain compared to T mice (4.06 ± 0.43 vs 0.38 ± 0.28 g, P < 0.01). WAT mass, adipocyte size, and the weights of gastrocnemius and soleus muscles, lung, kidney, and adrenal gland were not different. Liver and heart were larger and the spleen was smaller in T compared to S mice (P < 0.05). Food intake was higher in T than S mice (4.7 ± 0.2 vs 4.0 ± 0.3 g/animal, P < 0.05) but oxygen consumption at rest did not differ between groups. T animals showed higher serum leptin concentration compared to S animals (6.37 ± 0.5 vs 3.11 ± 0.12 ng/mL). WAT gene expression pattern obtained by transcription factor adipocyte determination and differentiation-dependent factor 1, fatty acid synthase, malic enzyme, hormone-sensitive lipase, adipocyte lipid binding protein, leptin, and adiponectin did not differ significantly between groups. Collectively, our results showed that PT prevents BW gain and maintains WAT mass due to an increase in food intake and unchanged resting metabolic rate. These responses are closely related to unchanged WAT gene expression patterns.

Changes in pre-pregnancy weight and weight gain during pregnancy: retrospective comparison between 1986 and 2004

QUESTIONS UNDER STUDY: To compare the incidence of pre-pregnancy overweight, obesity, and difference in weight gain during pregnancy in the years 1986 and 2004, in women delivered at the maternity unit of our hospital. METHODS: Retrospective study. Maternity records of patients delivered in the years 1986 and 2004 were compared. Data extraction included booking weight, height, weight gain, birth weight as well as information on mode of delivery and gestational age at delivery. RESULTS: During the year 1986 and 2004 a total of 690 and 668 patients respectively were included in the analysis. The pre-pregnancy BMI > or =25 doubled over the 18-year period (from 15.9 to 30.1%). In 1986 only 2.6% of all pregnant women gained more than 20 kg, while in 2004 14.2% (p <0.0001) did so. The caesarean section rate was significantly higher in 2004 than 18 years earlier (28.3 and 9.3%, p <0.0001). CONCLUSIONS: We found a significant increase in all parameters between these two groups. Pregnant women are today heavier at the booking visit, are more overweight, and gain more weight during pregnancy. A similar trend is seen in the newborn babies, who have a higher birth weight than those born 18 years ago.

Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children

BACKGROUND Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. OBJECTIVES We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). METHODS First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. RESULTS Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). CONCLUSION Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.

The joint influence of gender and amount of smoking on weight gain one year after smoking cessation

Weight gain is often associated with smoking cessation and may discourage smokers from quitting. This study estimated the weight gained one year after smoking cessation and examined the risk factors associated with weight gain in order to identify socio-demographic groups at higher risk of increased weight after quitting. We analyzed data from 750 adults in two randomized controlled studies that included smokers motivated to quit and found a gradient in weight gain according to the actual duration of abstinence during follow-up. Subjects who were abstinent for at least 40 weeks gained 4.6 kg (SD = 3.8) on average, compared to 1.2 kg (SD = 2.6) for those who were abstinent less than 20 weeks during the 1-year follow-up. Considering the duration of abstinence as an exposure variable, we found an age effect and a significant interaction between sex and the amount of smoking before quitting: younger subjects gained more weight than older subjects; among light smokers, men gained more weight on average than women one year after quitting, while the opposite was observed among heavy smokers. Young women smoking heavily at baseline had the highest risk of weight gain after quitting.

Age-specific and sex-specific weight gain norms to monitor antiretroviral therapy in children in low-income and middle-income countries.

BACKGROUND Viral load and CD4% are often not available in resource-limited settings for monitoring children's responses to antiretroviral therapy (ART). We aimed to construct normative curves for weight gain at 6, 12, 18, and 24 months following initiation of ART in children, and to assess the association between poor weight gain and subsequent responses to ART. DESIGN Analysis of data from HIV-infected children younger than 10 years old from African and Asian clinics participating in the International epidemiologic Databases to Evaluate AIDS. METHODS The generalized additive model for location, scale, and shape was used to construct normative percentile curves for weight gain at 6, 12, 18, and 24 months following ART initiation. Cox proportional models were used to assess the association between lower percentiles (< 50th) of weight gain distribution at the different time points and subsequent death, virological suppression, and virological failure. RESULTS Among 7173 children from five regions of the world, 45% were underweight at baseline. Weight gain below the 50th percentile at 6, 12, 18, and 24 months of ART was associated with increased risk of death, independent of baseline characteristics. Poor weight gain was not associated with increased hazards of virological suppression or virological failure. CONCLUSION Monitoring weight gain on ART using age-specific and sex-specific normative curves specifically developed for HIV-infected children on ART is a simple, rapid, sustainable tool that can aid in the identification of children who are at increased risk of death in the first year of ART.

Treatment intensification with insulin glargine in patients with inadequately controlled type 2 diabetes improves glycaemic control with a high treatment satisfaction and no weight gain

PRINCIPLES We aimed to evaluate the efficacy of, and treatment satisfaction with, insulin glargine administered with SoloSTAR® or ClikSTAR® pens in patients with type 2 diabetes mellitus managed by primary care physicians in Switzerland. METHODS A total of 327 patients with inadequately controlled type 2 diabetes were enrolled by 72 physicians in this prospective observational study, which aimed to evaluate the efficacy of a 6-month course of insulin glargine therapy measured as development of glycaemic control (glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG]) and weight change. We also assessed preference for reusable or disposable pens, and treatment satisfaction. RESULTS After 6 months, the mean daily dose of insulin glargine was 27.7±14.3 U, and dose titration was completed in 228 (72.4%) patients. Mean HbA1c decreased from 8.9%±1.6% (n=327) to 7.3%±1.0% (n=315) (p<0.0001), and 138 (43.8%) patients achieved an HbA1c≤7.0%. Mean FPG decreased from 10.9±4.5 to 7.3±1.8 mmol/l (p<0.0001). Mean body weight did not change (85.4±17.2 kg vs 85.0±16.5 kg; p=0.11). Patients' preference was in favour of the disposable SoloStar® pen (80%), as compared with the reusable ClickStar® pen (20%). Overall, 92.6% of physicians and 96.3% of patients were satisfied or very satisfied with the insulin glargine therapy. CONCLUSIONS In patients with type 2 diabetes insulin glargine administered by SoloSTAR® or ClikSTAR® pens, education on insulin injection and on self-management of diabetes was associated with clinically meaningful improvements in HbA1c and FPG without a mean collective weight gain. The vast majority of both patients and primary care physicians were satisfied with the treatment intensification.

A review of effective weight loss and/or weight gain prevention for disadvantaged populations

Introduction. The prevalence of overweight and obesity has increased sharply for both adults and children, particularity in disadvantaged populations. Changes in dietary habits are small; however applying behavior-change principles has been associated with weight loss and preventing weight gain. This article will review studies targeting economically disadvantaged and/or communities of color incorporating the Transtheoretical Model of Change (TTM).^ Methods. Inclusion criteria were established. Descriptions of characteristics of the reviewed study interventions are included.^ Results. The search yielded a total of 23 articles identified through the electronic database PubMed that included Transtheoretical Model of Change (TTM) interventions regarding diet and/or nutrition, physical activity and/or exercise in disadvantaged populations. Thirteen study interventions centered solely on diet modification, five focused only on physical activity, and five concentrated on a combination of both. The preponderance of studies targeted WIC and urban recipients.^ Discussion/Conclusion. Although the majority of intervention studies supported the use of the Transtheoretical Model of Change (TTM) for weight loss and preventing weight gain, researchers noted that challenges still exist and further interventions are needed.^

Adult weight gain and risk of colon cancer in men

Previous research supports the hypothesis that a "rich" diet (i.e., high in fat and low in fiber) increases the risk of colon cancer. Previous research also supports the hypothesis that physical inactivity increases the risk of colon cancer, perhaps because physical inactivity decreases gut motility, thereby increasing tee time that carcinogens are in contact with the intestinal mucosa. Habitual physical inactivity, combined with rich diet, ordinarily results in chronic energy imbalance and gain in weight, except when energy balance is modified by disease or factors such as cigarette smoking. Cigarette smokers typically stay lean because of effects of smoking on the resting metabolic rate as well as on efficiency of caloric intake and storage. Therefore, if physical inactivity and rich diet do increase the risk of colon cancer, then weight gain during young adulthood should be positively associated with incidence of colon cancer during later life, especially in nonsmokers.^ This hypothesis was investigated in a cohort of 2,059 randomly selected middle-aged men who were employed at the Western Electric Company in Chicago and were free of clinically diagnosed cancer at initial examination in 1958. Body mass index (BMI) in middle age was calculated from measured height and weight at the initial examination. BMI at age 20 was estimated from weight at age 20 as recalled at the initial examination and height as measured at the initial examination. Change in BMI between age 20 and middle age was estimated by subtracting the BMI at 20 from the BMI in middle age. Forty-nine incident cases of colon cancer were detected during 25 years (43,326 person-years) at risk. When stratified by level of change in BMI from age 20 to middle age ($\le$1.9, 2.0-3.9, 4.0-5.9, $\ge$6.0 kg/m$\sp2$), age-adjusted relative hazards of colon cancer in never-smokers were 1.00, 1.22, 2.31, and 5.01, respectively (p for trend = 0.008); corresponding values in ever-smokers were 1.00, 0.95, 0.77, and 0.87, These associations did not change appreciably after further adjustment for BMI at age 20, subscapular-triceps skinfold ratio, cigarette smoking, consumption of alcohol, energy, fat, and calcium.^ We also investigated the hypothesis that the risk of colon cancer was higher in men who were lean at age 20 and became fat by middle age (lean-to-fat) than in men who were fat at age 20 and stayed fat in middle-age (fat-to-fat). "Lean" was defined as BMI $<$24 kg/m$\sp2$ at age 20 and as BMI $<$27.0 kg/m$\sp2$ in middle age. Among never-smokers, in comparison to men who were lean at age 20 and in middle age (lean-to-lean), the age-adjusted relative hazard of colon cancer was 1.43 in the fat-to-fat group (95% confidence interval (CI) 0.37-5.52) and 3.36 in the lean-to-fat group (95% CI 1.21-9.37). This investigation provides new results on the magnitude of risk of colon cancer associated with weight gain during adulthood (from age 20 to middle age). This relation was obscured or underestimated in previous studies due to effect-modification by cigarette smoking. Finally, the result supports the idea that a life-style characterized by chronic energy imbalance during young adulthood increases risk of colon cancer. ^

SOCIAL AND BIOLOGICAL DETERMINANTS OF SHORT-TERM GROWTH VELOCITY AMONG PRESCHOOLERS OF RURAL GUATEMALA: A PATH ANALYSIS APPROACH (WEIGHT-GAIN, IRON DEFICIENCY, GASTROINTESTINAL SYMPTOMS)

This dissertation develops and tests through path analysis a theoretical model to explain how socioeconomic, socioenvironmental, and biologic risk factors simultaneously influence each other to further produce short-term, depressed growth in preschoolers. Three areas of risk factors were identified: child's proximal environment, maturational stage, and biological vulnerability. The theoretical model represented both the conceptual framework and the nature and direction of the hypotheses. Original research completed in 1978-80 and in 1982 provided the background data. It was analyzed first by nested-analysis of variance, followed by path analysis. The study provided evidence of mild iron deficiency and gastrointestinal symptomatology in the etiology of depressed, short-term weight gain. Also, there was evidence suggesting that family resources for material and social survival significantly contribute to the variability of short-term, age-adjusted growth velocity. These results challenge current views of unifocal intervention, whether for prevention or control. For policy formulations, though, the mechanisms underlying any set of interlaced relationships must be decoded. Theoretical formulations here proposed should be reassessed under a more extensive research design. It is suggested that studies should be undertaken where social changes are actually in progress; otherwise, nutritional epidemiology in developing countries operates somewhere between social reality and research concepts, with little grasp of its real potential. The study stresses that there is a connection between substantive theory, empirical observation, and policy issues. ^

Role of obesity, weight gain, physical activity, and polymorphisms in the mTOR pathway and the risk of renal cell carcinoma

The interplay between obesity, physical activity, weight gain and genetic variants in mTOR pathway have not been studied in renal cell carcinoma (RCC). We examined the associations between obesity, weight gain, physical activity and RCC risk. We also analyzed whether genetic variants in the mTOR pathway could modify the association. Incident renal cell carcinoma cases and healthy controls were recruited from the University of Texas MD Anderson Cancer Center in Houston, Texas. Cases and controls were frequency-matched by age (±5 years), ethnicity, sex, and county of residence. Epidemiologic data were collected via in-person interview. A total of 577 cases and 593 healthy controls (all white) were included. One hundred ninety-two (192) SNPs from 22 genes were available and their genotyping data were extracted from previous genome-wide association studies. Logistic regression and regression spline were performed to obtain odds ratios. Obesity at age 20, 40, and 3 years prior to diagnosis/recruitment, and moderate and large weight gain from age 20 to 40 were each significantly associated with increased RCC risk. Low physical activity was associated with a 4.08-fold (95% CI: 2.92-5.70) increased risk. Five single nucleotide polymorphisms (SNPs) were significantly associated with RCC risk and their cumulative effect increased the risk by up to 72% (95% CI: 1.20-2.46). Strata specific effects for weight change and genotyping cumulative groups were observed. However, no interaction was suggested by our study. In conclusion, energy balance related risk factors and genetic variants in the mTOR pathway may jointly influence susceptibility to RCC. ^

Association between sugar-sweetened beverages and both gestational weight gain and gestational diabetes

This cross-sectional study aimed at evaluating the association between sugar sweetened beverage (SSB) consumption and both excessive gestational weight gain (EGWG) and gestational diabetes mellitus (GDM). The study was conducted in the postpartum units of Memorial Hermann Hospital, Lyndon Baines Johnson General Hospital, the University of Texas Medical Branch at Galveston General Hospital, and the University of Texas at Brownsville Hospital. Between June 2009 and September 2010, women between the ages of 18 and 49 years with singleton pregnancies who delivered an infant born at 37 weeks of gestation or later were approached. Descriptive, univariate and multivariate analysis were employed in our study using the Statistical Analysis System (SAS) software version 9.1 (SAS Institute Inc. Cary, North Carolina). Our investigation did not find statistically significant associations between SSBs and EGWG. Our study reported no evidence of an association between SSBs and GDM except for sports drinks. However, the estimate of this association was deemed very imprecise. In conclusion, our study did not find strong provide strong support for the hypothesis that high consumption of SSBs increases the risk of EGWG or GDM. ^