Reducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice.

Although most adults can lose weight by dieting, a well-characterized compensatory decrease in energy expenditure promotes weight regain more than 90% of the time. Using mice with impaired hypothalamic leptin signaling as a model of early-onset hyperphagia and obesity, we explored whether this unfavorable response to weight loss could be circumvented by early intervention. Early-onset obesity was associated with impairments in the structure and function of brown adipose tissue mitochondria, which were ameliorated by weight loss at any age. Although decreased sympathetic tone in weight-reduced adults resulted in net reductions in brown adipose tissue thermogenesis and energy expenditure that promoted rapid weight regain, this was not the case when dietary interventions were initiated at weaning. Enhanced energy expenditure persisted even after mice were allowed to resume overeating, leading to lasting reductions in adiposity. These findings reveal a time window when dietary interventions can produce metabolic improvements that are stably maintained.

High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury.

INTRODUCTION: Increasing obesity and type 2 diabetes, in part due to the high-fat (HF) Western diet, parallels an increased incidence of osteoarthritis (OA). This study was undertaken to establish a causal relation between the HF diet and accelerated OA progression in a mouse model and to determine the relative roles of weight gain and metabolic dysregulation in this progression. METHODS: Five-week-old C57BL/6 mice were placed on HF (60% kcal) or low-fat (lean, 10% kcal) diets for 8 or 12 weeks before transecting the medial collateral ligament and excising a segment of the medial meniscus of the knee to initiate OA. One group was switched from lean to HF diet at the time of surgery. RESULTS: Body weight of mice on the HF diet peaked at 45.9 ± 2.1 g compared with 29.9 ± 1.8 g for lean diets, with only those on the HF becoming diabetic. Severity of OA was greater in HF mice, evidenced by the Osteoarthritis Research Society International (OARSI) histopathology initiative scoring method for mice and articular cartilage thickness and area. To assess the importance of weight gain, short- and long-term HF diets were compared with the lean diet. Short- and long-term HF groups outweighed lean controls by 6.2 g and 20.5 g, respectively. Both HF groups became diabetic, and OA progression, evidenced by increased OARSI score, decreased cartilage thickness, and increased osteophyte diameter, was comparably accelerated relative to those of lean controls. CONCLUSIONS: These results demonstrate that the HF diet accelerates progression of OA in a type 2 diabetic mouse model without correlation to weight gain, suggesting that metabolic dysregulation is a comorbid factor in OA-related cartilage degeneration.

Strategies for recognition of stem-loop RNA structures by synthetic ligands: application to the HIV-1 frameshift stimulatory sequence.

Production of the Gag-Pol polyprotein in human immunodeficiency virus (HIV) requires a -1 ribosomal frameshift, which is directed by a highly conserved RNA stem-loop. Building on our discovery of a set of disulfide-containing peptides that bind this RNA, we describe medicinal chemistry efforts designed to begin to understand the structure-activity relationships and RNA sequence-selectivity relationships associated with these compounds. Additionally, we have prepared analogues incorporating an olefin or saturated hydrocarbon bioisostere of the disulfide moiety, as a first step toward enhancing biostability. The olefin-containing compounds exhibit affinity comparable to the lead disulfide and, importantly, have no discernible toxicity when incubated with human fibroblasts at concentrations up to 1 mM.