No abstract

Overweight and obesity have the largest association with physical function measures. Recent national standards, which have lowered the threshold for defining overweight, identify patients who are more likely to have clinically significant reductions in HRQOL and functional impairment.

Context Although commercial weight loss programs provide treatment to millions of clients, their efficacy has not been evaluated in rigorous long-term trials. Objective To compare weight loss and health benefits achieved and maintained through self-help weight loss vs with a structured commercial program.

Although obesity has multiple etiologies, an overlooked possibility is an infectious origin. We previously identified two viruses, SMAM-1, an avian adenovirus (Ad), and Ad-36, a human adenovirus, that produce a syndrome of visceral obesity, with paradoxically decreased serum cholesterol and triglycerides in chickens and mice. In the two studies presented in this paper, we used nonhuman primates to investigate the adiposity-promoting potential of Ad-36. In study 1, we observed spontaneously occurring Ad-36 antibodies in 15 male rhesus monkeys, and a significant longitudinal association of positive antibody status with weight gain and plasma cholesterol lowering during the 18 mo after viral antibody appearance. In study 2, which was a randomized controlled experiment, three male marmosets inoculated with Ad-36 had a threefold body weight gain, a greater fat gain and lower serum cholesterol relative to baseline (P <0.05) than three uninfected controls at 28 wk postinoculation. These studies illustrate that the adiposity-promoting effect of Ad-36 occurs in two nonhuman primate species and demonstrates the usefulness of nonhuman primates for further evaluation of Ad-36-induced adiposity.

Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro‐opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo‐controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of β‐endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.