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Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein ␣-subunit (Gs␣), the G protein required for receptor-stimulated cAMP production; extralarge Gs␣ (XL␣s), a paternally expressed Gs␣ isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G s␣ undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2 m؊/؉ ) or paternal (E2 ؉/p؊ ) allele results in opposite effects on energy metabolism. E2 m؊/؉ mice are obese and hypometabolic, whereas E2 ؉/p؊ mice are lean and hypermetabolic. We now studied the effects of Gs␣ deficiency without disrupting other Gnas gene products by deleting G s␣ exon 1 (E1). E1 ؉/p؊ mice lacked the E2 ؉/p؊ phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2 ؉/p؊ phenotype appears to result from XL␣s deficiency, whereas loss of paternalspecific Gs␣ expression in E1 ؉/p؊ mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2 m؊/؉ mice, E1 m؊/؉ mice had s.c. edema at birth, presumably due to loss of maternal Gs␣ expression. However, E1 m؊/؉ mice differed from E2 m؊/؉ mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1 m؊/؉ mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1 ؉/p؊ mice. Differences between E1 m؊/؉ and E1 ؉/p؊ mice presumably result from differential effects on Gs␣ expression in tissues where Gs␣ is normally imprinted.G protein ͉ genomic imprinting ͉ pseudohypoparathyroidism

Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15-90 mg), nortriptyline (25 -100 mg), their combination, and a benztropine "active placebo" (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0-10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was 14% for nortriptyline (95% CI= [−2%, 30%]), 7% for morphine (95% CI= [−8%, 22%]), and 7% for the combination treatment (95% CI= [−4%, 18%]). Mean doses were: nortriptyline alone, 84 +/− 24.44 (SD)mg/day; morphine alone, 62 +/−29mg/day; and combination, morphine, 49 +/−27 mg/day plus nortriptyline, 55 mg+/− 33.18 mg/ day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.

Background Controversy exists regarding the optimal rate of weight loss for long-term weight management success. Purpose This study examined whether gradual initial weight loss was associated with greater long-term weight reduction than rapid initial loss. Methods Groups were drawn from participants in the TOURS trial, which included a sample of middle-aged (mean =59.3 years) obese women (mean BMI =36.8) who received a 6-month lifestyle intervention followed by a 1-year extended care program. Participants were encouraged to reduce caloric intake to achieve weight losses of 0.45 kg/ week. Groups were categorized as “FAST” (≥0.68 kg/week, n=69), “MODERATE” (≥0.23 and <0.68 kg/week, n= 104), and “SLOW” (<0.23 kg/week, n=89) based on rate of weight loss during first month of treatment. Results The FAST, MODERATE, and SLOW groups differed significantly in mean weight changes at 6 months (−13.5, −8.9, and −5.1 kg, respectively, ps <0.001), and the FAST and SLOW groups differed significantly at 18 months (−10.9, −7.1, and −3.7 kg, respectively, ps <0.001). No significant group differences were found in weight regain between 6 and 18 months (2.6, 1.8, and 1.3 kg, respectively, ps < 0.9). The FAST and MODERATE groups were 5.1 and 2.7 times more likely to achieve 10% weight losses at 18 months than the SLOW group. Conclusion Collectively, findings indicate both short- and long-term advantages to fast initial weight loss. Fast weight losers obtained greater weight reduction and long-term maintenance, and were not more susceptible to weight regain than gradual weight losers.

The G protein G s α is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver G s -signaling pathways by developing mice with liver-specific G s α deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARγ coactivator-1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide-1 levels and pancreatic α cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic G s -signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.

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ObjectiveTo examine the contributions of frequency, consistency, and comprehensiveness of dietary self-monitoring to long-term weight change.Design and MethodsParticipants included 220 obese women (mean±SD, age=59.3±6.1 years; BMI=36.8±4.9 kg/m2) who achieved a mean loss of -10.39±5.28% from baseline during 6 months of behavioral treatment and regained 2.30±7.28% during a 12-month extended-care period. The contributions of cumulative frequency (total number of food records) of self-monitoring, consistency across time (number of weeks with ≥3 records), and comprehensiveness of information recorded were examined as predictors of weight regain in a hierarchical linear regression analysis The mediating role of adherence to daily caloric intake goals was tested using a bootstrapping analysis.ResultsThe association between high total frequency of self-monitoring and reduced weight regain was moderated by weekly consistency of self-monitoring, p=.004; increased frequency produced beneficial effects on weight change only when coupled with high consistency (>3 days/week). There was no impact of comprehensiveness on weight change, p>.05. The favorable effect of high frequency/high consistency self-monitoring on weight change was partially mediated by participants’ success in meeting daily caloric intake goals (p< .001).ConclusionThe combination of high frequency plus high consistency of dietary self-monitoring improves long-term success in weight management.

Objective: To assess whether group dynamics are associated with weight loss, session attendance, and self-monitoring adherence after 6 months of lifestyle intervention for obesity. Methods: Women with obesity (N 5 125; mean 6 SD BMI 5 37.84 6 3.94 kg/m 2 ; age 5 51.99 6 10.81 years) participated in a 24-week group-based lifestyle weight loss intervention and achieved a weight loss of 9.13 6 7.15 kg after 6 months. Participants reported their perceptions of group conflict, avoidance, engagement, social support, and attraction at the end of treatment. Multiple regression with forward selection assessed which group dynamic variables were associated with weight loss, attendance, and adherence. Results: Greater perceived group conflict was associated with smaller weight losses (b 5 1.833, P 5 0.044) and lower attendance (b 5 22.313, P 5 0.002) and adherence rates (b 5 22.261, P 5 0.030). Higher group attraction was associated with higher attendance rates (b 5 0.051, P 5 0.039). The association between perceived conflict and weight change was mediated by attendance and adherence (P 5 0.019). Conclusions: Findings demonstrate that group dynamics associate with weight loss outcomes, attendance, and adherence. Addressing conflicts and fostering acceptance among group members may promote success in group-based lifestyle interventions for obesity.