Compositions and methods for white to beige adipogenesis
Inventors
Cooper, Denise Ratzlaff • Kirchoffer, Ryan Adam • Sparks, Robert Pleasants • Guida, Wayne Charles
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-10828304-B2
Publication Date
2020-11-10
Expiration Date
2038-03-26
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Abstract
Disclosed herein are compositions and methods for transitioning or converting a white adipocyte to a beige adipocyte. The compositions and methods may be used in the treatment of obesity. In some embodiments, the compositions include a compound selected from DC677 and DC761.
Core Innovation
The invention relates to compositions and methods for converting white adipocytes into beige adipocytes. The compositions include compounds such as DC677 and DC761, which are specific inhibitors of the kinase Clk1. These compounds promote the differentiation of white adipose tissue (WAT) into beige adipose tissue, characterized by increased mitochondrial biogenesis and the expression of proteins such as UCP1 and PGC1α, which are involved in energy dissipation rather than storage.
The background identifies obesity as a serious and prevalent global health problem associated with numerous comorbidities including type 2 diabetes, cardiovascular diseases, hypertension, and certain cancers. Current treatment options for obesity and adipogenesis are limited, and there exists a need for new therapies. The invention addresses this need by providing methods and compositions that target the molecular processes underlying adipocyte differentiation, specifically by inhibiting Clk1 to promote the formation of energy-burning beige adipocytes from white adipocytes.
Claims Coverage
The patent includes four independent claims directed to methods of inhibiting Clk1, reducing or treating obesity, reducing BMI, and converting white adipocytes into beige adipocytes using specified compounds. These claims define inventive features related to the compounds' specificity, mechanism of action, and resulting biological effects.
Method of inhibiting Clk1 using specific compounds
Administering to a subject a compound selected from DC677, DC761, or their pharmaceutically acceptable salts or combinations thereof to inhibit Clk1 activity specifically without inhibiting Clk2, Clk3, or Clk4.
Method of reducing or treating obesity via Clk1 inhibition
Administering the compounds DC677, DC761, or pharmaceutically acceptable salts or combinations to a subject to reduce or treat obesity by increasing expression of UCP1 and PGC1α, reducing lipid droplet size, and decreasing lipid storage in adipocytes relative to a control.
Method of reducing body mass index (BMI) using specified compounds
Administering the compounds DC677, DC761, or pharmaceutically acceptable salts or combinations to a subject to reduce BMI with effects including Clk1 inhibition and associated changes in adipocyte lipid storage and gene expression.
Method of converting white adipocytes to beige adipocytes
Administering the specified compounds to white adipocytes to induce their differentiation into beige adipocytes by inhibiting Clk1, increasing UCP1 and PGC1α expression, reducing size of lipid droplets, and decreasing lipid storage compared to controls.
The claims collectively cover the use of specific Clk1 inhibitory compounds to modulate adipocyte differentiation and treat obesity-related conditions by promoting the transition from white to beige adipocytes with defined molecular and cellular effects.
Stated Advantages
The compounds specifically inhibit Clk1 without inhibiting Clk2, Clk3, or Clk4, providing targeted activity.
The method promotes mitochondrial biogenesis and increases expression of thermogenic proteins (UCP1 and PGC1α) leading to energy dissipation rather than fat storage.
Treatment with the compounds reduces lipid droplet size and lipid accumulation in adipocytes, contributing to anti-obesity effects.
The compounds can efficiently induce adipocyte beiging during terminal differentiation with relatively short exposure times and at nanomolar concentrations.
Documented Applications
Treatment or prevention of obesity in subjects by promoting the conversion of white adipose tissue to beige adipose tissue.
Methods to reduce body mass index (BMI) in subjects through administration of Clk1 inhibitory compounds.
Conversion or differentiation of white adipocytes into beige adipocytes to stimulate energy expenditure.
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