Planned care for obesity and cardiovascular risk reduction using a stepped-down approach: A randomized-controlled trial.

Primary care-based approaches to address concurrent obesity and cardiovascular disease risk factors (CVDRFs) that begin with a high intensity intervention that is subsequently decreased (i.e., stepped-down) if weight loss is achieved have not been rigorously examined. Our study is a 20-month, single-blind randomized controlled trial at five primary care clinics in San Diego, CA, in 2013, where 262 obese adults (aged 25-70 years; 32.1% male; 59.2% white) with at least one CVDRF were enrolled into planned care for obesity and risk reduction (PCORR) using a stepped-down approach or enhanced usual care (EUC). All patients received physician recommendations for weight loss and CVDRFs. EUC patients (n = 132) received an individual session with a health educator every 4 months. PCORR patients (n = 130) received individual and group sessions (in-person, mail, telephone, and email) in three steps, characterized by less contact if success was achieved. At 20 months, 40.7%, 23.8%, and 15.4% of PCORR patients were in steps 1, 2, and 3, respectively (25.2% were lost to follow-up). PCORR resulted in a between-group difference in reduction in body weight of 6.1% [95% CI, 5.3 to 6.9] compared to EUC 2.8% [95% CI, 2.0 to 3.6] p = 0.007, with a greater reduction in BMI (35.2 [95% CI, 34.4 to 35.9] to 33.7 [95% CI, 32.9 to 34.5] kg/m2) than EUC (36.0 [95% CI, 35.3 to 36.8] to 35.1 [95% CI, 34.3 to 35.9] kg/m2), as indicated by a significant treatment by time interaction (p = 0.009). PCORR resulted in greater weight loss over 20 months than EUC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01134029.

Schizosaccharomyces pombe adenylate cyclase suppressor mutations suggest a role for cAMP phosphodiesterase regulation in feedback control of glucose/cAMP signaling.

Mutations affecting the Schizosaccharomyces pombe cAMP phosphodiesterase (PDE) gene cgs2+ were identified in a screen for suppressors of mutant alleles of the adenylate cyclase gene (git2+/cyr1+), which encode catalytically active forms of the enzyme that cannot be stimulated by extracellular glucose signaling. These mutations suppress both the git2(-) mutant alleles used in the suppressor selection and mutations in git1+, git3+, git5+, git7+, git10+, and git11+, which are all required for adenylate cyclase activation. Notably, these cgs2 mutant alleles fail to suppress mutations in gpa2+, which encodes the Galpha subunit of a heterotrimeric G protein required for adenylate cyclase activation, although the previously identified cgs2-2 allele does suppress loss of gpa2+. Further analysis of the cgs2-s1 allele reveals a synthetic interaction with the gpa2(R176H)-activated allele, with respect to derepression of fbp1-lacZ transcription in glucose-starved cells. In addition, direct measurements of cAMP levels show that cgs2-s1 cells maintain normal basal cAMP levels, but are severely defective in feedback regulation upon glucose detection. These results suggest that PDE activity in S. pombe may be coordinately regulated with adenylate cyclase activity as part of the feedback regulation mechanism to limit the cAMP response to glucose detection.