Novelty: Identification of PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium, and as a potential target in the treatment of obesity.
Value Proposition: Obesity is a chronic, complex, serious disease, and has become one of the major epidemics and contributor to the global burden of disease and morbidity. This disease segment is one with a huge unmet clinical need and a wide prevalence. Available approved drugs targeting obesity is very limited and there is a need to find novel targets and development of more safe and effective drugs for treatment of obesity. To this end, researchers at The University of Toledo have identified a novel biological target for the treatment of obesity that will help develop drug molecules for the treatment of this metabolic disorder. It has been discovered that PP5 reciprocally modulates the lipometabolic activities of GRα and PPARγ – nuclear receptors that are antagonists of lipid metabolism. Research studies have also shown that:
· PP5 interacts with both GRα and PPARγ controlling their states of phosphorylation.
· PP5 inhibits the lipolytic activity of GRα but promotes the lipogenic activity of PPARγ.
· Absence of PP5 results in a complete inability of cells to accumulate lipid.
· PP5 deficient mice have increased femoral bone density with decreased lipid content in bone marrow adipose cells.
· Drug inhibition of PP5 could be used to treat obesity, diabetes, or osteoporosis.
Invention description: It is known that glucocorticoid (GR) and peroxisome proliferator-activated (PPARγ) receptors are antagonists of lipid metabolism and regulate adipogenesis by controlling the balance between lipolysis and lipogenesis. Research conducted at The University of Toledo has shown that protein phosphatase 5 (PP5), a nuclear receptor co-chaperone, reciprocally modulates the lipometabolic activities of GRα and PPARγ. Elevated expression of PP5 was found in adipose of mice subjected to high fat diet and in 3T3-L1 exposed to adipogenic stimuli. Importantly, stimulated PP5 knock out cells showed almost no lipid accumulation with reduced expression of adipogenic markers (aP2, CD36, perilipin) and low fatty acid synthase enzymatic activity. These phenotypes were completely reversed in PP5KO cells following reintroduction of PP5 .
Studies in mice with global ablation (KO) of PP5 have provided additional evidence that PP5 is a key regulator of lipid metabolism. PP5-KO mice maintained on a regular chow diet demonstrated reduced weight gain with age that was attributable to lower percent body fat with increased percent lean muscle mass. Reduced fasting glycaemia was also observed that correlated with improved glucose and insulin tolerance. Calorimetric analysis showed elevated spontaneous activity and energy expenditure in the KO animals. Lastly, analysis of bone revealed increased femur bone density with almost complete absence bone marrow fat cells. These results suggest that drug inhibition of PP5 could be used to treat obesity, diabetes, or osteoporosis.
Validity of PP5 as the target for metabolic diseases is also shown by another research group where researchers have shown that PP5 deficiency in mice is associated with reduced weight gain, lower fasting glycaemia, and improved glucose tolerance during IPGTT .
Looking for partners: To advance this technology and develop new therapeutics for the obesity and diabetes.
IP status: Patent pending
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