Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6–8 weeks of age were fed a high fat (n= 18) or regular (n= 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P= 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH;P= 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH;P< 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.
Hyperinsulinemic hypoglycemia is a recently described complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that glucagon administration would help maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output, and if so, represent a new therapeutic option for postbypass hypoglycemia. In this study, we compared the insulin and glycemic response to a mixed meal with and without concomitant glucagon infusion in a patient with severe recurrent hypoglycemia after RYGB. Although effective in transiently raising postprandial plasma glucose values, glucagon infusion was also associated with higher insulin concentrations, and failed to prevent symptomatic hypoglycemia. This case demonstrates that glucagon may have limited clinical utility in the treatment of post-RYGB hyperinsulinemic hypoglycemia.
Physical fitness is often inversely associated with adiposity in children cross-sectionally, but the effect of becoming fit or maintaining fitness over time on changes in weight status has not been well studied in children. We investigated the impact of changes in fitness over 1–4 years of follow-up on the maintenance or achievement of healthy weight among 2,793 schoolchildren who were first measured as 1st to 7th graders. Students were classified as “fit” or “underfit” according to age- and gender-specific norms in five fitness domains: endurance, agility, flexibility, upper body strength, and abdominal strength. Weight status was dichotomized by BMI percentile: “healthy weight” (<85th percentile) or “overweight/obese” (≥85th percentile). At baseline, of the 38.3% overweight/obese children, 81.9% (N= 875) were underfit. Underfit overweight students were more likely to achieve healthy weight if they achieved fitness (boys: odds ratio (OR) = 2.68, 95% confidence interval (CI) = 1.24–5.77; girls: OR = 4.67, 95%CI = 2.09–10.45). Initially fit overweight children (N= 194) were more likely to achieve healthy weight if they maintained fitness (boys: OR = 11.99, 95%CI = 2.18–65.89; girls: OR = 2.46, 95%CI = 1.04–5.83). Similarly, initially fit healthy-weight children (N= 717) were more likely to maintain healthy weight if they maintained fitness (boys: OR 3.70, 95%CI = 1.40–9.78; girls: OR = 4.14, 95%CI = 1.95–8.78). Overweight schoolchildren who achieve or maintain physical fitness are more likely to achieve healthy weight, and healthy-weight children who maintain fitness are more likely to maintain healthy weight. School-based policies/practices that support physical fitness may contribute to obesity reduction and maintenance of healthy weight among schoolchildren.
Although obesity is associated with overactivation of the white adipose tissue (WAT) renin–angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies andin vitrostudies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NF κB-dependent increases in WAT inflammation.
This 56-week, randomized, placebo-controlled trial examined the efficacy and safety of naltrexone plus bupropion as an adjunct to intensive behavior modification (BMOD). A total of 793 participants (BMI = 36.5 ± 4.2 kg/m2) was randomly assigned in a 1:3 ratio to: (i) placebo + BMOD (N= 202); or (ii) naltrexone sustained-release (SR, 32 mg/day), combined with bupropion SR (360 mg/day) plus BMOD (i.e., NB32 + BMOD;N= 591). Both groups were prescribed an energy-reduced diet and 28 group BMOD sessions. Co-primary end points were percentage change in weight and the proportion of participants who lost ≥5% weight at week 56. Efficacy analyses were performed on a modified intent-to-treat population (ITT; i.e., participants with ≥1 postbaseline weight while taking study drug (placebo + BMOD,N= 193; NB32 + BMOD,N= 482)). Missing data were replaced with the last observation obtained on study drug. At week 56, weight loss was 5.1 ± 0.6% with placebo + BMOD vs. 9.3 ± 0.4% with NB32 + BMOD (P< 0.001). A completers analysis revealed weight losses of 7.3 ± 0.9% (N= 106) vs. 11.5 ± 0.6% (N= 301), respectively (P< 0.001). A third analysis, which included all randomized participants, yielded losses of 4.9 ± 0.6 vs. 7.8 ± 0.4%, respectively (P< 0.001). Significantly more NB32 + BMOD- vs. placebo + BMOD-treated participants lost ≥5 and ≥10% of initial weight, and the former had significantly greater improvements in markers of cardiometabolic disease risk. NB32 + BMOD was generally well tolerated, although associated with more reports of nausea than placebo + BMOD. The present findings support the efficacy of combined naltrexone/bupropion therapy as an adjunct to intensive BMOD for obesity.
Family based behavioral treatment for overweight and obese children includes parenting skills targeting the modification of child eating and activity change. The purpose of this study was to examine parenting skills and parent weight change as predictors of child weight change in a sample of 80 parent/child dyads who were enrolled in a family based behavioral weight loss program for childhood obesity. Eighty overweight and obese children and their parents who enrolled in treatment in two sites were included in the study. Variables included those related to parent modeling (parent BMI), home food environment, parenting (parent and child report), and demographics. Results suggested that parent BMI change was a significant predictor of child weight, in that a reduction of 1 BMI unit in the parent was associated with a 0.255 reduction in child BMI. None of the other variables were significant in the final model. This study is consistent with other research showing that parent weight change is a key contributor to child weight change in behavioral treatment for childhood obesity. Researchers and clinicians should focus on encouraging parents to lose weight to assist their overweight and obese child in weight management.
To evaluate the association between body mass index (BMI: kg/m2) and mortality among Hispanic adults, we acquired 8 years (1997–2004) of National Health Interview Survey data linked to public-use mortality follow-up data through 2006. Using Cox proportional hazards regression, we fit separate models for two attained age strata (18 to <60 years, ≥60 years) adjusting for sex, smoking, and physical activity with over 38,000 analyzable respondents. We found that, among those aged ≥60 years, underweight (BMI ≤ 18.5) associated with elevated mortality (hazard ratio HR] = 2.19; 95% confidence interval CI], 1.38–3.46) while overweight (BMI of 25 to <30) and obesity grade 1 (BMI of 30 to <35) associated with reduced mortality (HR’s = 0.79; 95% CI, 0.65–0.95 and 0.71; 95% CI, 0.56–0.91), respectively. There were no significant associations between BMI and mortality among the 18 to <60 years attained age strata or among never smokers for either age strata. Overweight and obesity are not obviously associated with elevated mortality among Hispanic adults.
SH2-B, a JAK2-interacting protein has recently been identified as a key regulator of leptin and insulin sensitivity, glucose homeostasis and body weight in mice. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the humanSH2Bgene are associated with these variables. A tagging SNP, Ala484Thr (rs7498665) was selected to represent five common SNPs (minor allele frequency (MAF) >0.05) in perfect linkage disequilibrium (LD) in a 16 kb region encompassing theSH2Bgene. The tSNP was genotyped in 2455 Caucasian female twins (mean age 47.4±12.6 years) from the St Thomas’ UK Adult Twin Registry (Twins UK). Ala484Thr (minor allele frequency 0.38) was associated with serum leptin, total fat, waist circumference and body weight (Ps=0.02–0.04). The coding SNP has no predicted effect on protein structure or function and is likely to be in LD with an as yet unidentified functional variant in theSH2Bgene. Our results support a role for SH2-B in modulating the regulation of body weight and fat by leptin in this female population. If SH2-B signalling is attenuated in diet-induced obesity, it could become a target for drug-induced leptin sensitization.