Diet-induced obese mice are leptin insufficient after weight reduction.

Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high-fat (HF) diet-induced obese (DIO) mice were switched to a low-fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF-chow), but retained a greater amount of adiposity than chow-fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF-chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mass were lower in HF-chow mice. Leptin administration was used to test whether reduced leptin level of HF-chow mice inhibited further fat loss. Leptin treatment led to an additional reduction in adiposity. Finally, HF-HF mice had lower mRNA levels of beta(3) adrenergic receptor (beta(3)-AR) in epididymal WAT (EWAT) compared to chow-fed mice, and diet change led to an increase in the WAT beta(3)-AR mRNA levels that were similar to the levels of chow-fed mice, suggesting an elevation in sympathetic activation of WAT during diet switch relative to HF-HF mice leading to the reduced leptin level and proinflammatory cytokine content. In summary, HF-chow mice were resistant to further fat loss due to leptin insufficiency. Diet alteration from HF to low fat improved metabolic state of DIO mice, although their adiposity was defended at a higher level.

Aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists--Increasing selectivity over hERG.

A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.

Two novel paradigms for the simultaneous assessment of conditioned taste aversion and food intake effects of anorexic agents.

The conditioned taste aversion (CTA) is routinely used to assess the aversive consequences of anorexic agents, including potential pharmacological therapies for obesity. In a typical CTA paradigm, rats briefly sampling a novel tastant (e.g., saccharin) are acutely administered with toxin (e.g., lithium chloride, LiCl). After as few as one taste-toxin pairing, rats will reliably avoid the novel tastant. This paradigm is frequently used for the assessment of possible aversive consequences of drugs that are candidates for pharmacological therapies. The degree to which the drug supports development of a CTA is interpreted as an index of its aversive properties. Difficulties with previous work include the inability to assess affects on food intake and CTA simultaneously, particularly during chronic drug administration. We report here two novel CTA paradigms for the assessment of appetitive and aversive consequences of anorexic agents, simultaneously. In the first experiment, animals receive an intraoral infusion of a novel and highly palatable tastant immediately prior to administration of increasing doses of LiCl. In the second experiment, rats were implanted intraperitoneally with osmotic minipumps that chronically delivered a low dose of LiCl for 7 days. LiCl did not affect short or long term food intake in either experiment. However, LiCl did support the development of a CTA in both paradigms. These results suggest that both the appetitive and aversive consequences of anorexic agents can be assessed simultaneously during either acute or chronic drug administration.

Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the beta2-adrenergic receptor.

Analyses were performed to evaluate the roles of the beta1- and beta2-adrenergic receptors in the skeletal muscle hypertrophy and anti-atrophy response to the beta-adrenergic agonist, clenbuterol. Treatment of wild-type mice with clenbuterol resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. Treatment of beta1-adrenergic receptor knockout mice with clenbuterol also resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. In contrast, in beta2-adrenergic receptor knockout mice and in mice lacking both the beta1- and beta2-adrenergic receptors, clenbuterol treatment did not result in hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles, nor did it inhibit denervation-induced atrophy in these muscles. Together these data demonstrate that the beta2-adrenergic receptor is responsible for both the skeletal muscle hypertrophy and anti-atrophy effects of the beta-adrenergic agonist clenbuterol.