The stereochemical structure of the molecule allows it to bind to two cognate receptors (prohibitin and ANXA-2) found exclusively on blood vessels of white adipose tissues. High tissue specificity prevents it from targeting the brown fat tissues present in the body. Thus it does not influence adaptive brown fat thermogenesis, which is crucial, especially for babies who can conserve only limited body heat. The body surface area to volume ratio promotes high rates of heat loss for them.
Adipotide & Obesity
In 2008, epidemiological studies revealed that 33.9% of the total American adult population suffered from obesity. Obesity results from an increase in excess adipose mass. Improved lean body mass can also cause an increase in weight but does not result in obesity. Obesity results in higher chances of morbidity and mortality. It is measured by the BMI (Body Mass Index), anthropometry (using skinfold thickness), and densitometry. BMI of 30 serves as a cut-off for obesity. Various health issues such as hypertension, hyperlipidemia, metabolic syndrome, NIDDM (Non-Insulin Dependent Diabetes Mellitus), cerebrovascular accidents, myocardial infarction, and cancers are associated with obesity. Interestingly, morbidity is determined by the distribution of adipose tissues and the waist-to-hip ratio of a person. Abdominal fat is more harmful than in lower limbs or buttocks because of its higher lipolytic function.
Adipose tissue comprises lipid storing adipocytes (cells) and vascular macrophages, and preadipocytes. An increase in adipose mass is caused by excess lipid deposition in adipocytes leading to hypertrophy and subsequent hyperplasia. It further triggers the infiltration of macrophages and conversion of preadipocytes to adipocytes. The blood supply also promotes this microenvironment. Adipotide targets this blood supply, thereby causing irreversible ischemic injury and apoptosis of adipose tissues.
Selected Research Studies
In 2004 a study named “Reversal of obesity by targeted ablation of adipose tissue” by Mikhail G Kolonin et al. observed that targeted apoptosis in the vascular bed of white adipose tissue could be used to treat obesity. Obese mice were administered a peptide CKGGRAKDC which binds to a multifunctional vascular membrane protein called prohibitin. It causes a decrease in adipose tissue mass and normalization of overall metabolic processes without any significant side effects. Thus the peptide might be helpful against human obesity as human beings also express prohibitin in their white adipose tissue vasculature.
Translation of anti-obesity therapies developed in rodents into therapeutics for humans is challenging due to their biological differences. Hence subjects of research should ideally also be primates. In 2011, research entitled “A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys” by Kirstin F. Barnhart et al. established the ligand-directed peptidomimetic named Adipotide (with sequence CKGGRAKDC-GG-D(KLAKLAK)2 ) as a prototype of anti-obesity peptides in obese monkeys. Adipotide was observed to cause apoptosis in the vasculature of white adipose tissue leading to rapid weight loss, improved insulin and renal function in the monkeys.
In 2011, Fernanda I. Staquicinia et al. analyzed vascular marker(s) for different organs in their work entitled “Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients.” The survey included 2.35 × 106 motifs from a peptide library in cancer patients for uncovering ligand-receptors specific to particular vascular beds. Among the 4 native ligand-receptors found, two were native ligand-receptors (cathepsin B/apolipoprotein E3 and integrin α4/annexin A4) that existed across tissues. The other two had tissue-specific prevalence – prohibitin/annexin A2 exclusive for the white adipose tissue and RAGE/leukocyte proteinase-3 found in bone metastases. Thus prohibitin and ANXA-2 were found to be receptors specific for vasculature of white fat tissue.
Adipotide is a peptidomimetic compound that exhibits pro-apoptotic and lipolytic properties allowing it to act as an anti-obesity peptide. Researches have shown that its mode of action includes selective apoptosis of the vasculature of the white adipose tissue. Thus, the blood supply to adipocytes gets compromised, leading to the adipocytes’ irreversible ischemic injury and apoptotic death. The death of white fat cells causes an overall reduction in adipose mass. Hence the peptide has the potential to be used for the treatment of human obesity.
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