Peptide Designed to Elicit Apoptosis in Adipose Tissue Endothelium Reduces Food Intake and Body Weight
Abstract
OBJECTIVE Because adipose tissue is highly vascularized, modifying adipose tissue vasculature may provide a novel method for reducing body fat. A peptide sequence that elicits apoptosis of endothelium in white fat potently reduced body weight. We sought to determine how inhibiting adipose tissue vasculature changes key aspects of energy balance regulation and the neuroendocrine system that maintains energy balance.
RESEARCH DESIGN AND METHODS Lean and obese mice or rats were treated with proapoptotic peptide for 4 or 27 days. Daily energy intake and expenditure were measured in mice on a low- (LFD) or high-fat diet (HFD) and in rats on a HFD. A conditioned taste aversion test was performed to assess whether proapoptotic peptide produces visceral illness. Hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocoritin (POMC) mRNA expression and plasma leptin levels were evaluated.
RESULTS Proapoptotic peptide completely reversed HFD-induced obesity in mice and reduced body weight in mice and rats on a HFD but not in those on a LFD. Fat loss occurred with no change of energy expenditure but reduced food intake that occurred without signs of illness and despite reduced circulating leptin and reduced hypothalamic POMC gene expression, indicating that the decrease in food intake is independent of the action of leptin.
CONCLUSIONS These experiments provide compelling evidence for a previously unknown relationship between the status of adipose tissue vasculature and the regulation of food intake.
The prevalence of overweight and obesity among adults and children is increasing throughout the developed world, highlighting the enormous need to find new therapeutic strategies that allow for safe and durable weight loss. However, chronic weight loss is difficult to achieve because of elaborate neuroendocrine mechanisms that work against sustained negative energy balance. We herein present data on a promising strategy to induce significant weight loss by inhibiting angiogenesis in adipose tissue. White adipose tissue is highly vascularized, and both the expansion and maintenance of adipose tissue depend on a continued ability to build the necessary vasculature to support a large volume of tissue. In this way, increasing adipose mass can be compared with an expanding tumor because both tissues require rapid angiogenesis. Given this dependence on the capacity to make new blood vessels, one successful strategy for reducing the size of tumors has been to inhibit angiogenesis and thereby starve tumors.
Pharmacological inhibitors of angiogenesis such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470) and angiostatin reduce fat mass in obese and leptin-deficient mice. Adopting an alternative strategy, Kolonin et al. used phage display to identify a peptide sequence that specifically homes to endothelial cells in white adipose tissue by binding to the cell-surface molecule prohibitin. This peptide sequence was then fused to a proapoptotic sequence that, when internalized in a cell, initiates apoptosis. Thus, they developed a “proapoptotic peptide” that specifically reduces endothelium and vasculature in white adipose tissue. When administered over a 4-week period, the proapoptotic peptide reduced body weight and fat mass of ob/ob mice and mice with diet-induced obesity without eliciting abnormal fat absorption. That report did not identify how the energy-balance equation was modified to achieve the dramatic weight loss . Thus, the present experiments sought to determine the relationship between adipose tissue vasculature and regulation of energy balance by identifying mechanisms of energy balance by which apoptosis selectively in endothelium of white adipose tissue results in profound weight loss.
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These results demonstrate that administering a peptide that produces apoptosis uniquely in the endothelium of white adipose tissue can produce profound reductions in body weight that are primarily in the form of reduced body fat. This reduction in body weight occurs through a decrease in food intake without signs of illness. In particular, mice made obese on a HFD can be returned to the body weight and nearly the body fat of mice maintained on a LFD. The ability to completely reverse diet-induced obesity is a result achieved by few other treatments and replicates the original reports using this proapoptotic peptide.
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Obesity remains a daunting problem. The current results, however, support the notion that starving adipose tissue of its necessary vasculature results in profound reductions in body weight and body fat. Of particular interest in the present studies is that administering a peptide designed to cause apoptosis in endothelial cells uniquely in white adipose tissue results in a reduction in caloric intake.
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