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BACKGROUND - With the introduction of integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy, persons living with HIV have a potent new treatment option. Recently, providers at our large treatment clinic noted weight gain in several patients who switched from efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). In this study, we evaluated weight change in patients with sustained virologic suppression who switched from EFV/TDF/FTC to an INSTI-containing regimen.
METHODS - We performed a retrospective observational cohort study among adults on EFV/TDF/FTC for at least 2 years who had virologic suppression. We assessed weight change over 18 months in patients who switched from EFV/TDF/FTC to an INSTI-containing regimen or a protease inhibitor (PI)-containing regimen versus those on EFV/TDF/FTC over the same period. In a subgroup analysis, we compared patients switched to DTG/ABC/3TC versus raltegravir- or elvitegravir-containing regimens.
RESULTS - A total of 495 patients were included: 136 who switched from EFV/TDF/FTC to an INSTI-containing regimen and 34 switched to a PI-containing regimen. Patients switched to an INSTI-containing regimen gained an average of 2.9 kg at 18 months compared with 0.9 kg among those continued on EFV/TDF/FTC (P = 0.003), whereas those switched to a PI regimen gained 0.7 kg (P = 0.81). Among INSTI regimens, those switched to DTG/ABC/3TC gained the most weight at 18 months (5.3 kg, P = 0.001 compared with EFV/TDF/FTC).
CONCLUSION - Adults living with HIV with viral suppression gained significantly more weight after switching from daily, fixed-dose EFV/TDF/FTC to an INSTI-based regimen compared with those remaining on EFV/TDF/FTC. This weight gain was greatest among patients switching to DTG/ABC/3TC.
OBJECTIVE - The purpose of the study was to explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of obesity induced by a high-fat diet (HFD).
METHODS - C57BL/6J wild-type, Cx3cr1 , Ccr2 , and Cx3cr1 Ccr2 double-knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12 weeks of age.
RESULTS - All groups gained weight at a similar rate and developed a similar degree of adiposity, hyperglycemia, glucose intolerance, and impairment of insulin sensitivity in response to HFD. As expected, the circulating monocyte count was decreased in Ccr2 and Cx3cr1 Ccr2 mice but not in Cx3cr1 mice. Flow cytometric analysis of perigonadal adipose tissue of male, but not female, mice revealed trends to lower CD11c+MGL1- M1-like macrophages and higher CD11c-MGL1+ M2-like macrophages as a percentage of CD45+F4/80+CD11b+ macrophages in Cx3cr1 Ccr2 mice versus wild-type mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes.
CONCLUSIONS - Although CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence the metabolic effects of a 45% HFD-induced obesity in these model conditions.
© 2017 The Obesity Society.
Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
Copyright © 2017 Elsevier B.V. All rights reserved.
Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD) and proopiomelanocortin neurons (GLP-1RKD). Chow-fed GLP-1RKD mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD and GLP-1RKD mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.
© 2017 by the American Diabetes Association.
BACKGROUND - Obesity prevalence is disproportionately high among Hispanic children.
OBJECTIVES - The Healthy Families Study assessed the efficacy of a culturally targeted, family-based weight gain prevention intervention for Hispanic immigrant families with children ages 5-7 years.
METHODS - The study used a two-group, cluster randomized trial design, assigning 136 families (clusters) to the active intervention (weight gain prevention) and 136 families to attention control (oral health). The active intervention included a 4-month intensive phase (eight classes) and an 8-month reinforcement phase (monthly mail/telephone contact). Children's body mass index z-score (BMI-Z) was the primary outcome.
RESULTS - The BMI-Z growth rate of the active intervention group did not differ from the attention control group at short-term follow-up (median 6 months; 168 families, 206 children) or long-term follow-up (median 16 months; 142 families, 169 children). Dose response analyses indicated a slower increase in BMI-Z at short term among overweight/obese children who attended more intervention classes. Moderate physical activity on weekends increased at short term. Weekend screen time decreased at short term among those attending at least one class session.
CONCLUSION - Low class attendance likely impacted intention-to-treat results. Future interventions targeting this population should test innovative strategies to maximize intervention engagement to produce and sustain effects on weight gain prevention.
© 2016 World Obesity Federation.
General obesity, typically measured using body mass index (BMI), has been associated with an increased risk of several cancers. However, few prospective studies have been conducted in Asian populations. Although central obesity, often measured using waist-hip ratio (WHR), is more predictive for type 2 diabetes and cardiovascular diseases (CVD) risk than BMI, knowledge of its association with cancer incidence is limited. In a cohort of 68,253 eligible Chinese women, we prospectively investigated the association of BMI, WHR and weight change during adulthood with risk of overall cancer and major site-specific cancers using multivariate Cox proportional hazard models. Compared to the BMI group of 18.5-22.9 kg/m(2) , obese (BMI ≥ 30 kg/m(2) ) women were at an increased risk of developing overall cancer (hazard ratio = 1.36, 95% confidence interval = 1.21-1.52), postmenopausal breast cancer (HR: 2.43, 95% CI: 1.73-3.40), endometrial cancer (HR: 5.34, 95% CI: 3.48-8.18), liver cancer (HR: 1.93, 95% CI: 1.14-3.27) and epithelial ovarian cancer (HR: 2.44, 95% CI: 1.37-4.35). Weight gain during adulthood (per 5 kg gain) was associated with increased risk of all cancers combined (HR: 1.05, 95% CI: 1.03-1.08), postmenopausal breast cancer (HR: 1.17, 95% CI: 1.10-1.24) and endometrial cancer (HR: 1.37, 95% CI: 1.27-1.48). On the other hand, WHR was not associated with cancer risk after adjustment for baseline BMI. These findings suggest that obesity may be associated with cancer risk through different mechanisms from those for type 2 diabetes and CVD and support measures of maintaining health body weight to reduce cancer risk in Chinese women.
© 2016 UICC.
Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3(-/-) mice gained more weight relative to EP3(+/+) mice. Overall, EP3(-/-) mice had increased epididymal fat mass and adipocyte size; paradoxically, a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3(-/-) mice. The EP3(-/-) mice had increased macrophage infiltration, TNF-α, monocyte chemoattractant protein-1, IL-6 expression, and necrosis in their epididymal fat pads as compared with EP3(+/+) animals. Adipocytes isolated from EP3(+/+) or EP3(-/-) mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3(-/-) mice lacked PGE2-evoked inhibition of isoproterenol stimulated lipolysis compared with EP3(+/+). EP3(-/-) mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3(-/-) mice became hyperglycemic and hyperinsulinemic when compared with EP3(+/+) fed HFD, demonstrating a more severe insulin resistance phenotype in EP3(-/-). These results demonstrate that when fed a HFD, EP3(-/-) mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance.
The proportion of overweight and obese adults in the United States and Canada has increased over the past decade, but temporal trends in body mass index (BMI) and weight gain on antiretroviral therapy (ART) among HIV-infected adults have not been well characterized. We conducted a cohort study comparing HIV-infected adults in the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD) to United States National Health and Nutrition Examination Survey (NHANES) controls matched by sex, race, and age over the period 1998 to 2010. Multivariable linear regression assessed the relationship between BMI and year of ART initiation, adjusting for sex, race, age, and baseline CD4(+) count. Temporal trends in weight on ART were assessed using a generalized least-squares model further adjusted for HIV-1 RNA and first ART regimen class. A total of 14,084 patients from 17 cohorts contributed data; 83% were male, 57% were nonwhite, and the median age was 40 years. Median BMI at ART initiation increased from 23.8 to 24.8 kg/m(2) between 1998 and 2010 in NA-ACCORD, but the percentage of those obese (BMI ≥30 kg/m(2)) at ART initiation increased from 9% to 18%. After 3 years of ART, 22% of individuals with a normal BMI (18.5-24.9 kg/m(2)) at baseline had become overweight (BMI 25.0-29.9 kg/m(2)), and 18% of those overweight at baseline had become obese. HIV-infected white women had a higher BMI after 3 years of ART as compared to age-matched white women in NHANES (p = 0.02), while no difference in BMI after 3 years of ART was observed for HIV-infected men or non-white women compared to controls. The high prevalence of obesity we observed among ART-exposed HIV-infected adults in North America may contribute to health complications in the future.
Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight-sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter-regulatory response to insulin through restoration of the hepatic-peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight-sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review.
© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.