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Adipotide is a peptidomimetic compound that has been shown to possess pro-apoptotic properties that do cause weight loss in rhesus monkeys and mice. Its sequence is CKGGRAKDC-GG-D(KLAKLAK)2. Studies have shown that its mode of action involves the selective apoptosis of blood vessels supplying the white adipose tissue. Adipotide causes such vessels to undergo atrophy (shrinkage) and eventually apoptosis (cell death), thus cutting off the blood supply to the fat cells. This results in ischemic injury, which is a lack of blood supply and oxygen to the fat cells. The effects are non-reversible, so the fat cells also undergo apoptosis or cell death.
Molecular analysis has shown that the stereo-chemical structure of Adipotide enables it to bind to two specific receptors that are exclusively found in blood vessels that supply white adipose tissue. These receptors are prohibitin and ANXA-2. Due to the tissue specificity of these receptors, Adipotide does not have any effect on the brown adipose tissue, thus it does not affect the adaptive brown fat thermogenesis. Brown fat thermogenesis is especially vital for babies because they have limited capacity for heat conservation as the body surface area to volume ration favors high rates of heat loss. The white adipose tissue is formed only when energy consumption exceeds energy utilization.
Obesity
In 2008, epidemiological studies showed that 33.9% of the total American adult population is affected by obesity. Obesity results from excess adipose tissue mass. Studies have shown that white adipose tissue is the main cause of obesity. An increase in body weight does not equate to obesity since such an increase could result from an increase in the lean body mass and not necessarily due to increased adiposity. Obesity is associated with an increase in morbidity and mortality rates. Currently, obesity is gauged using the BMI (Body Mass Index), anthropometry (using skinfold thickness) and densitometry. The threshold for obesity is set at a BMI of 30. Increased adiposity predisposes the affected individual to a myriad of pathologies such as hypertension, hyperlipidemia, metabolic syndrome, NIDDM (Non-Insulin Dependent Diabetes Mellitus), cerebrovascular accidents, myocardial infarction and cancers. The distribution of adiposity does determine the morbidity rate, for instance abdominal adiposity causes more morbidity than adiposity localized to the buttocks and lower limbs. Therefore, the waist-to-hip ratio is used clinically to determine the probability of a person being affected by the pathologies stated above. The association between abdominal adiposity to increased morbidity is attributed to the fact that intra-abdominal adipocytes possess more lipolytic activity as compared to adipocytes located in the lower limbs.
Adipose tissue is made up of adipocytes (lipid-storing adipose cells) and the vascular/stromal compartment where macrophages and preadipocytes reside. Hypertrophy of adipose cells due to increased lipid deposition, and their subsequent hyperplasia do result in an increase in adipose mass. Such an increase is also characterized by high numbers of infiltrating macrophages and increased differentiation of preadipocytes to adipocytes. Such differentiation and maintenance of an increased adipose mass is sustained by an intact blood supply to the adipose tissue. Ischemic injury to such an adipose tissue would inhibit differentiation and activate apoptotic cascades in the injured adipocytes. Therefore, a peptidomimetic such as Adipotide would cause a reduction in adipose mass by causing non-reversible ischemic injury to adipocytes located in white adipose tissue. This can be inferred from the studies analyzed below:
Selected Research Studies
In 2004, Mikhail G Kolonin et al conducted a study entitled “Reversal of obesity by targeted ablation of adipose tissue”. The findings of this study were published in the peer-reviewed academic journal Nature Medicine. The aim of this study was to show that a targeted induction of vascular apoptosis in the vascular bed of white adipose tissue could be used as anti-obesity therapy. The subjects of this study were mice. The study used an isolate of a peptide motif whose sequence (CKGGRAKDC) enabled it to selectively target white adipose tissue vasculature. In-vivo phage display was used to isolate the peptide motif. The study results revealed that the peptide motif associates with a multifunctional membrane protein called prohibitin. It thus established that prohibitin was a vascular marker of white adipose tissue vasculature. Results also revealed that the targeting of the white adipose tissue vasculature by the pro-apoptotic peptide did result in the ablation of the adipose tissue mass. The resorption of the white fat did lead to a normalization of the overall metabolic processes. Such normalization occurred without any significant adverse effects. It could be inferred from the study that since human beings also express prohibitin in their white adipose tissue vasculature, then the studied peptide motif would also cause ablation of their white fat mass. However, studies are currently ongoing to develop an equivalent anti-obesity therapy that could be used in humans.
Rodents and primates do differ biologically and this creates significant difficulties in translating anti-obesity therapies developed in rodents into therapeutics that can be administered to humans. These difficulties are reduced if the subjects studied were also members of the primate family. This occurred in 2011, when Kirstin F. Barnhart et al conducted a study entitled “A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys”. The findings of the study were published in Science Translational Medicine. In this study, a ligand-directed peptidomimetic was evaluated for its actions in obese monkeys. The sequence of the ligand-directed peptidomimetic was CKGGRAKDC-GG-D(KLAKLAK)2 which was also named Adipotide. The results of the study revealed that Adipotide did induce apoptosis in the vasculature of white adipose tissue with a resultant rapid loss of weight and improved insulin function in the monkeys. Reduction in white adipose tissue mass was confirmed by MRI (Magnetic resonance imaging) and DEXA (dual-energy x-ray absorptiometry). Results also showed an improvement in the renal function of the monkeys. Thus, this study did establish that Adipotide can be considered as a prototype of anti-obesity peptides.
In 2011, Fernanda I. Staquicinia et al did conduct a study entitled “Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients” where vascular markers for the different organs were analyzed. The study involved screening of the peptide library in patients suffering from cancer with the aim of uncovering ligand-receptors specific to particular vascular beds. A survey of approximately 2.35 × 106 motifs derived from biopsies did yield a non-random distribution pattern which indicated that it was possible to target specific systemic vascular beds. Further analysis using similarity search, affinity chromatography and protein arrays did reveal 4 native ligand-receptors. Two of these native ligand-receptors (cathepsin B/apolipoprotein E3 and integrin α4/annexin A4) were distributed in multiple tissues. The other two receptors showed a restricted specific distribution with prohibitin/annexin A2 being restricted to white adipose tissue and RAGE/leukocyte proteinase-3 being restricted to bone metastases. Annexin A2 is usually abbreviated as ANXA-2. Therefore, this study does show that the receptors expressed in the vasculature of white fat are prohibitin and ANXA-2.
Conclusion
Adipotide is a peptidomimetic compound [sequence CKGGRAKDC-GG-D(KLAKLAK)2] that possesses pro-apoptotic and lipolytic properties which enables it to act as an anti-obesity peptide. Studies have shown that its mode of action involves selective apoptosis of the vasculature of the white adipose tissue. This results in apoptosis in the white fat cells, thus reducing the overall adipose mass.
Molecular analysis has shown that the stereo-chemical structure of Adipotide enables it to bind to two specific receptors that are exclusively found in blood vessels that supply white adipose tissue. These receptors are prohibitin and ANXA-2. Due to the tissue specificity of these receptors, Adipotide does not have any effect on the brown adipose tissue, thus it does not affect the adaptive brown fat thermogenesis. Brown fat thermogenesis is especially vital for babies because they have limited capacity for heat conservation as the body surface area to volume ration favors high rates of heat loss. The white adipose tissue is formed only when energy consumption exceeds energy utilization.
Obesity
In 2008, epidemiological studies showed that 33.9% of the total American adult population is affected by obesity. Obesity results from excess adipose tissue mass. Studies have shown that white adipose tissue is the main cause of obesity. An increase in body weight does not equate to obesity since such an increase could result from an increase in the lean body mass and not necessarily due to increased adiposity. Obesity is associated with an increase in morbidity and mortality rates. Currently, obesity is gauged using the BMI (Body Mass Index), anthropometry (using skinfold thickness) and densitometry. The threshold for obesity is set at a BMI of 30. Increased adiposity predisposes the affected individual to a myriad of pathologies such as hypertension, hyperlipidemia, metabolic syndrome, NIDDM (Non-Insulin Dependent Diabetes Mellitus), cerebrovascular accidents, myocardial infarction and cancers. The distribution of adiposity does determine the morbidity rate, for instance abdominal adiposity causes more morbidity than adiposity localized to the buttocks and lower limbs. Therefore, the waist-to-hip ratio is used clinically to determine the probability of a person being affected by the pathologies stated above. The association between abdominal adiposity to increased morbidity is attributed to the fact that intra-abdominal adipocytes possess more lipolytic activity as compared to adipocytes located in the lower limbs.
Adipose tissue is made up of adipocytes (lipid-storing adipose cells) and the vascular/stromal compartment where macrophages and preadipocytes reside. Hypertrophy of adipose cells due to increased lipid deposition, and their subsequent hyperplasia do result in an increase in adipose mass. Such an increase is also characterized by high numbers of infiltrating macrophages and increased differentiation of preadipocytes to adipocytes. Such differentiation and maintenance of an increased adipose mass is sustained by an intact blood supply to the adipose tissue. Ischemic injury to such an adipose tissue would inhibit differentiation and activate apoptotic cascades in the injured adipocytes. Therefore, a peptidomimetic such as Adipotide would cause a reduction in adipose mass by causing non-reversible ischemic injury to adipocytes located in white adipose tissue. This can be inferred from the studies analyzed below:
Selected Research Studies
In 2004, Mikhail G Kolonin et al conducted a study entitled “Reversal of obesity by targeted ablation of adipose tissue”. The findings of this study were published in the peer-reviewed academic journal Nature Medicine. The aim of this study was to show that a targeted induction of vascular apoptosis in the vascular bed of white adipose tissue could be used as anti-obesity therapy. The subjects of this study were mice. The study used an isolate of a peptide motif whose sequence (CKGGRAKDC) enabled it to selectively target white adipose tissue vasculature. In-vivo phage display was used to isolate the peptide motif. The study results revealed that the peptide motif associates with a multifunctional membrane protein called prohibitin. It thus established that prohibitin was a vascular marker of white adipose tissue vasculature. Results also revealed that the targeting of the white adipose tissue vasculature by the pro-apoptotic peptide did result in the ablation of the adipose tissue mass. The resorption of the white fat did lead to a normalization of the overall metabolic processes. Such normalization occurred without any significant adverse effects. It could be inferred from the study that since human beings also express prohibitin in their white adipose tissue vasculature, then the studied peptide motif would also cause ablation of their white fat mass. However, studies are currently ongoing to develop an equivalent anti-obesity therapy that could be used in humans.
Rodents and primates do differ biologically and this creates significant difficulties in translating anti-obesity therapies developed in rodents into therapeutics that can be administered to humans. These difficulties are reduced if the subjects studied were also members of the primate family. This occurred in 2011, when Kirstin F. Barnhart et al conducted a study entitled “A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys”. The findings of the study were published in Science Translational Medicine. In this study, a ligand-directed peptidomimetic was evaluated for its actions in obese monkeys. The sequence of the ligand-directed peptidomimetic was CKGGRAKDC-GG-D(KLAKLAK)2 which was also named Adipotide. The results of the study revealed that Adipotide did induce apoptosis in the vasculature of white adipose tissue with a resultant rapid loss of weight and improved insulin function in the monkeys. Reduction in white adipose tissue mass was confirmed by MRI (Magnetic resonance imaging) and DEXA (dual-energy x-ray absorptiometry). Results also showed an improvement in the renal function of the monkeys. Thus, this study did establish that Adipotide can be considered as a prototype of anti-obesity peptides.
In 2011, Fernanda I. Staquicinia et al did conduct a study entitled “Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients” where vascular markers for the different organs were analyzed. The study involved screening of the peptide library in patients suffering from cancer with the aim of uncovering ligand-receptors specific to particular vascular beds. A survey of approximately 2.35 × 106 motifs derived from biopsies did yield a non-random distribution pattern which indicated that it was possible to target specific systemic vascular beds. Further analysis using similarity search, affinity chromatography and protein arrays did reveal 4 native ligand-receptors. Two of these native ligand-receptors (cathepsin B/apolipoprotein E3 and integrin α4/annexin A4) were distributed in multiple tissues. The other two receptors showed a restricted specific distribution with prohibitin/annexin A2 being restricted to white adipose tissue and RAGE/leukocyte proteinase-3 being restricted to bone metastases. Annexin A2 is usually abbreviated as ANXA-2. Therefore, this study does show that the receptors expressed in the vasculature of white fat are prohibitin and ANXA-2.
Conclusion
Adipotide is a peptidomimetic compound [sequence CKGGRAKDC-GG-D(KLAKLAK)2] that possesses pro-apoptotic and lipolytic properties which enables it to act as an anti-obesity peptide. Studies have shown that its mode of action involves selective apoptosis of the vasculature of the white adipose tissue. This results in apoptosis in the white fat cells, thus reducing the overall adipose mass.
