Reversal of Obesity by Targeted Ablation of Adipose Tissue

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Obesity is an increasingly prevalent human condition in developed societies. Despite major progress in the understanding of the molecular mechanisms leading to obesity, no safe and effective treatment has yet been found. Here, we report an antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue.

We used in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes to white fat vasculature. We show that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establish prohibitin as a vascular marker of adipose tissue.

Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients.
Introduction

Diet and lifestyle contribute to the high incidence of obesity in the developed world. In the United States, approximately 65% of the adult population is overweight, with a body mass index of greater than or equal to 25 kg/m2, and over 30% is obese (body mass index of greater than or equal to 30 kg/m2). Obesity is associated with increased risk for diabetes mellitus, cancer and heart disease, and it often causes shortening of human life. Advances in the treatment of obesity have thus far been rather limited with few drugs available to control abnormal fat accumulation. Most antiobesity agents are based on altering energy balance pathways and appetite by acting on receptors in the brain. Some drugs of this class (such as fenfluramine) have been withdrawn from the market due to unexpected toxicity. Recent attempts to develop compounds that inhibit absorption of fat through the gastrointestinal tract (such as orlistat) may improve antiobesity treatment. Still, even the most effective drugs can only reduce weight by up to 5%, and strict dieting is required for further weight loss.

We sought to develop a strategy that would form the basis for an improved antiobesity therapy. Proliferation of tumor cells depends on new blood vessel formation (angiogenesis) that accompanies malignant progression. Indeed, anticancer therapies using angiogenesis inhibitors or cytotoxic agents targeted to the vasculature of tumors are currently being evaluated in clinical trials. Although white fat is a nonmalignant tissue, it has the capability to quickly proliferate and expand. Histological evaluation of adipose tissue reveals that fat is highly vascularized: multiple capillaries make contacts with every adipocyte, suggesting the importance of blood vessels for maintenance of the tissue mass. Indeed, Rupnick et al. recently showed that nonspecific angiogenesis inhibitors can prevent the development of obesity in mice, and regulation of hepatic tissue mass by angiogenesis has also been reported.

We reasoned that targeting existing blood vessels in white fat could result in adipose tissue ablation. Here, we selected peptide ligands that bind to receptors in white fat vasculature. We show that targeted delivery of a chimeric peptide containing a proapoptotic sequence to the fat vasculature of obese mice resulted in obesity reversal and metabolic normalization. We also identify prohibitin as the vascular receptor for the peptide ligand white fat tissue.

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