Compositions and methods for modulating metabolic pathways
Inventors
Zemel, Michael • Grindstaff, II, E. Douglas • Bruckbauer, Antje
Assignees
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Publication Number
US-9855235-B2
Publication Date
2018-01-02
Expiration Date
Abstract
Compositions and methods useful for inducing an increase in fatty acid oxidation or mitochondrial biogenesis, reducing weight gain, inducing weight loss, or increasing Sirt1, Sirt3, or AMPK activity are provided herein. Such compositions can contain synergizing amounts of a sirtuin-pathway activators, including but not limited to resveratrol, in combination with beta-hydroxymethylbutyrate (HMB), keto isocaproic acid (KIC), leucine, or combinations of HMB, KIC and leucine.
Core Innovation
The invention relates to a method for treating obesity in a subject in need thereof by administering a composition that includes leucine and/or one or more metabolites thereof, together with a sirtuin pathway activator. The composition is formulated as a tablet, capsule, gel capsule, beverage, snack bar, or a food composition, and is substantially free of the individual amino acids alanine, glutamic acid, glycine, isoleucine, valine, and proline.
The leucine metabolites are selected from keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB. The composition includes at least about 0.5 mg of a sirtuin pathway activator and defines molar ratio constraints between leucine or leucine metabolites and the sirtuin pathway activator component.
The document further describes sirtuin-pathway activating compounds and pharmaceutical compositions that modulate sirtuin pathways, including activator selection from polyphenol or polyphenol precursor group and named examples such as resveratrol and piceatannol. It also describes sirtuin/AMPK activation agents and metabolic pathway effects associated with sirtuin signaling, including mitochondrial biogenesis and fatty acid oxidation.
A particular concept in the document is combining leucine or leucine metabolites with sirtuin-pathway activators to increase mitochondrial biogenesis and fatty acid oxidation and to modulate metabolic, insulin, and inflammation endpoints. The document names leucine metabolites including HMB, KIC, and alpha-hydroxy-isocaproic acid, and it describes synergy effects on SIRT1 and SIRT3 activity and mitochondrial and fat-oxidation outcomes for leucine metabolites in combination with resveratrol.
Claims Coverage
The independent claim coverage centers on a treatment method for obesity using a composition that combines leucine and/or selected leucine metabolites with a sirtuin pathway activator, while using defined formulation forms, substantial amino-acid exclusions, and leucine/metabolite molar ratio constraints. Across the provided claim content, four inventive features are identified.
Obesity treatment using leucine or leucine metabolites plus a sirtuin pathway activator
A method for treating obesity in a subject in need thereof by administering a composition containing at least about 500 mg of leucine and/or at least about 200 mg of one or more metabolites thereof, where the leucine metabolites are selected from KIC, alpha-hydroxy-isocaproic acid, and HMB, and an amount of at least about 0.5 mg of a sirtuin pathway activator.
Composition formulated for oral and food formats with specified amino-acid exclusion
The composition is formulated as a tablet, capsule, gel capsule, beverage, snack bar or a food composition, and is substantially free of the individual amino acids alanine, glutamic acid, glycine, isoleucine, valine, and proline.
Defined molar-ratio constraints for leucine-metabolite to activation component
When the leucine component is a metabolite of leucine, the molar ratio of the leucine component to the sirtuin pathway activator component is greater than 10; and when the leucine component is leucine, the molar ratio of leucine to the sirtuin pathway activator component is greater than 500.
Sirtuin-pathway activator targets SIRT1, SIRT3, AMPK, and PGC1α
The sirtuin pathway activator activates one or more of SIRT1, SIRT3, AMPK, and PGC1α.
The inventive focus is an obesity-treatment method based on administering a composition that pairs leucine and/or specific leucine metabolites with a sirtuin pathway activator, while meeting substantially-free amino-acid requirements and specified leucine/metabolite molar ratio constraints. The activator is characterized by activation of one or more of SIRT1, SIRT3, AMPK, and PGC1α.
Stated Advantages
Synergistic enhancement of mitochondrial biogenesis.
Improvement in metabolic outcomes including fat oxidation and insulin sensitivity.
Reduced inflammation and oxidative stress.
Increased muscle glucose uptake.
Increased vasodilation and body temperature.
Documented support in cells and diet-induced obese/diabetic mouse models.
Supports fat browning (including FNDC5/irisin-related markers).
Improves obesity/weight outcomes.
Documented Applications
Treating obesity in a subject in need thereof by administering the defined composition.
Obesity treatment characterized by reductions in body weight, weight gain, visceral adipose tissue mass, and fat oxidation/heat production measures, and respiratory exchange ratio.
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