Whereas a detailed mechanism of motion for adipotide remedy remains to be fully elucidated, we noticed that weight loss in obese rhesus monkeys occurred concurrently with a discount in meals intake. Strikingly, lean rhesus monkeys receiving a therapeutic dose of adipotide didn’t drop pounds (fig. S5). This discovering suggests that the mechanism of motion may be obesity-particular in primates.
Previously, paired-feeding experiments in obese rodents (16, 17) additionally indicated decreased food intake as a attainable contributor to weight loss in mice and rats handled with adipotide. Adipotide remedy was usually nicely tolerated in all three species of nonhuman primates examined. The primary aspect effect, renal toxicity, was generally mild and reversible. Decreased serum phosphorus and potassium and urinary modifications that included mild-to-marked glucosuria, mild-to-reasonable proteinuria, and a slight-to-mild improve in transitional/renal epithelial cells have been noted all through the dosing interval. These findings, which were indicative of altered proximal tubular perform and tubular damage, resolved during the recovery period.
Clinical evidence of dehydration at the best dose examined is suggestive of a decreased glomerular filtration charge (GFR); nonetheless, a reduction in GFR is usually accompanied by an elevation of both BUN and serum creatinine. Given the elevation of serum creatinine without a concurrent and commensurate improve in BUN in obese monkeys treated with adipotide, we thought-about other potential mechanisms corresponding to elevated loss of urea and/or decreased reabsorption of creatinine within the proximal tubule.
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MRI and DEXA imaging confirmed that weight loss in the rhesus monkeys occurred primarily because of visceral fat loss. Given the speedy loss of adipose tissue over a brief period of time, one might need expected an abnormal enhance in serum-free fatty acids and possibly dyslipidemia due to rapid fats mobilization.
Surprisingly, free fatty acid concentrations confirmed a reducing development all through the remedy interval (fig. S4A), in keeping with the traditional metabolic processing of excess adipose tissue. Similar trends were noted for monounsaturated fatty acids as well as many polyunsaturated fatty acids. With the speedy reduction in white adipose tissue observed, the potential for abnormal fecal elimination of lipids was thought-about. For drugs that inhibit intestinal absorption of fat from meals, excess fecal lipids have resulted in undesirable unwanted effects that embody oily stools, flatulence, fecal incontinence, and diarrhea.
Whereas fecal lipids had been indirectly measured in our nonhuman primate research, the absence of these unwanted side effects was considered inconsistent with elevated fecal elimination of lipids after adipotide administration. In abstract, we exhibit by anthropometric measurements and imaging that adipotide rapidly induces weight loss that’s attributable to a marked discount in the amount of white adipose tissue in obese nonhuman primates. The weight loss can also be accompanied by a modest discount in serum-free fatty acids and an enchancment in insulin resistance.