A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys

A peptide-based drug that targets the vasculature of adipose tissue induces weight loss and improves metabolic function in spontaneously obese monkeys. Fat Monkeys Get Trim The rapidly increasing rate of obesity worldwide is one of the biggest health challenges facing society today. Unlike related threats such as cancer, cardiovascular disease, and diabetes, very few approved drugs are available to treat obesity despite some promising early-stage candidates. In a new study, Barnhart and colleagues take a fresh approach to treating obesity by developing a peptide-like molecule that targets the blood vessels that feed fat tissue. They test their peptidomimetic called adipotide in obese monkeys and show that it both reduces fat tissue and decreases resistance to insulin. Adipotide is a short peptide-based agent that selectively targets a receptor expressed by the vascular endothelial cells that comprise the blood vessels that support subcutaneous and visceral fat. This peptidomimetic carries a molecule that, once internalized by the endothelial cells, causes them to undergo programmed cell death, thereby inducing gradual elimination of excess fat. In placebo-controlled experiments, spontaneously obese rhesus monkeys treated with adipotide for 28 days showed a 7 to 15% weight loss as well as improved insulin resistance. Two forms of imaging revealed that the weight loss occurred primarily through a reduction in fat tissue and did not reflect fluid loss or muscle wasting. Monkeys treated with adipotide displayed a 38% reduction in total body fat and a 27% reduction in abdominal fat compared to pretreatment baseline values. Early weight loss drug candidates are typically screened in rodent models of obesity. However, the central nervous system control and metabolic regulation of food intake and fat storage in rodents is quite different from that of monkeys and humans. Spontaneously obese monkeys are a more accurate model of obesity in humans and provide a valuable setting for testing anti-obesity drug candidates. Adipotide therapy resulted in a reduction in body mass, an improvement in insulin resistance, and a decrease in abdominal circumference, key predictors of diabetes in humans. These encouraging results support the further development of adipotide as a potential new prototype drug to combat obesity in humans. Obesity, defined as body mass index greater than 30, is a leading cause of morbidity and mortality and a financial burden worldwide. Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Biological differences between rodents and primates are a major hurdle for translation of anti-obesity strategies either discovered or developed in rodents into effective human therapeutics. Here, we evaluate the ligand-directed peptidomimetic CKGGRAKDC-GG-D(KLAKLAK)2 (henceforth termed adipotide) in obese Old World monkeys. Treatment with adipotide induced targeted apoptosis within blood vessels of white adipose tissue and resulted in rapid weight loss and improved insulin resistance in obese monkeys. Magnetic resonance imaging and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue. At experimentally determined optimal doses, monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans.