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-10675283-B2
Publication Date
2020-06-09
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 through the inhibition of Clk1, a protein kinase involved in alternative splicing. The compositions include compounds such as DC677 and DC761, which specifically inhibit Clk1 without inhibiting Clk2, Clk3, or Clk4. The transition from white to beige adipocytes is characterized by increased expression of thermogenic genes like UCP1 and PGC1α, reduced lipid droplet size, increased mitochondrial biogenesis, and reduced alternative splicing of specific proteins such as PKCβ1. This transition aims to convert energy-storing white fat into energy-dissipating beige fat.
The problem being addressed is obesity, a serious public health issue associated with numerous co-morbidities including diabetes, cardiovascular disease, and other metabolic disorders. Existing treatments for obesity are limited, and there is a significant need for new therapies targeting adipogenesis. Obesity results from excessive energy intake leading to enlarged and increased numbers of white adipocytes that store lipids. The invention addresses this problem by providing compounds and methods that promote the differentiation of white adipocytes into beige adipocytes, which burn energy through thermogenesis, potentially reducing obesity and related complications.
The disclosed methods include administering compounds that inhibit Clk1 to subjects in order to promote beige adipocyte differentiation within white adipose tissue, thereby increasing mitochondrial number and expression of UCP1 and PGC1α, markers associated with energy dissipation. The compounds induce beiging by blocking alternative splicing, reducing lipid droplet size, and lowering lipid storage in adipocytes. Pharmaceutical compositions containing these compounds are also provided for the treatment or prevention of obesity and for reducing body mass index.
Claims Coverage
The patent includes four primary independent claims directed to methods and compositions involving specific compounds for inhibiting Clk1, treating obesity, reducing BMI, and converting white adipocytes to beige adipocytes. These claims focus on the use of compounds DC677, DC761, and their pharmaceutically acceptable salts or combinations.
Methods for inhibiting Clk1 in a subject
Administering to a subject in need a compound selected from DC677, DC761, or their pharmaceutically acceptable salts or combinations to specifically inhibit Clk1.
Methods for reducing or treating obesity in a subject
Administering to a subject a compound selected from DC677, DC761, or their pharmaceutically acceptable salts or combinations, wherein Clk1 is inhibited but Clk2, Clk3, or Clk4 are not inhibited.
Methods for reducing body mass index (BMI) in a subject
Administering to a subject a compound selected from DC677, DC761, or their pharmaceutically acceptable salts or combinations causing inhibition of Clk1 without inhibiting Clk2, Clk3, or Clk4.
Methods for converting white adipocytes into beige adipocytes
Administering to white adipocytes a compound selected from DC677, DC761, or their pharmaceutically acceptable salts or combinations to inhibit Clk1, increasing expression of UCP1 and PGC1α, reducing lipid droplet size, and decreasing lipid storage.
Pharmaceutical compositions comprising specific Clk1 inhibitors
Compositions comprising compounds DC677, DC761, or their pharmaceutically acceptable salts with pharmaceutically acceptable carriers, that inhibit Clk1 but do not inhibit Clk2, Clk3, or Clk4.
The claims collectively cover the use of specific compounds DC677 and DC761 and their salts for selectively inhibiting Clk1 to promote white to beige adipocyte conversion, treat obesity, reduce BMI, and pharmaceutical compositions thereof, emphasizing specificity for Clk1 without affecting related kinases Clk2-4.
Stated Advantages
The compounds specifically inhibit Clk1 without inhibiting related kinases Clk2, Clk3, or Clk4, providing targeted therapeutic effect.
The methods induce beige adipocyte differentiation characterized by increased mitochondrial biogenesis and elevated UCP1 and PGC1α expression, promoting energy dissipation.
The compounds reduce lipid droplet size and lipid storage in adipocytes, thus converting energy-storing white fat to energy-burning beige fat.
Treatment with the compounds offers potential for reducing obesity and body mass index in subjects.
Documented Applications
Treatment or prevention of obesity by administering compounds that inhibit Clk1 to promote white to beige adipogenesis.
Reducing body mass index (BMI) in subjects through the administration of Clk1 inhibiting compounds.
Pharmaceutical compositions comprising Clk1 inhibitors for use in obesity treatment.
Converting white adipocytes to beige adipocytes in vitro or in vivo by administering compounds DC677, DC761 or their salts.
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