Compositions and methods for modulating metabolic pathways
Inventors
Zemel, Michael • Grindstaff, II, E. Douglas • Bruckbauer, Antje
Assignees
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Publication Number
US-10383837-B2
Publication Date
2019-08-20
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 disclosed subject matter relates to sirtuin activator compounds and sirtuin-pathway activating compounds described by multiple structural series defined by chemical formulas with variable substituents. The series include stilbene/chalcone compounds of Formula 1, flavanone-family compounds of Formula 2, isoflavones of Formula 3 and Formula 5, flavones of Formula 4, anthocyanidins of Formula 6, combined stilbene/chalcone/flavone representations of Formula 7, broader lists of other sirtuin-modulating compounds by formulas 8–25 and 30, alternative amide/aryl ring frameworks identified by Formula 31 and Formula 32, and a further class identified as Formula (III).
The disclosed compositions modulate metabolic pathways by combining a sirtuin-pathway activator, optionally a sirtuin activator selected from resveratrol and polyphenols, with branched-chain amino acids and/or one or more branched-chain amino acid metabolites. The metabolite components include leucine metabolites selected from keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB (beta-hydroxymethylbutyrate), and the approach emphasizes synergistic combinations that increase sirtuin-pathway output including SIRT1, SIRT3, AMPK, and PGC1α (PGC1-α).
The invention provides synergistic metabolic compositions for oral use that include specified amounts of leucine and/or leucine metabolites and an anti-diabetic agent. The compositions are formulated to be substantially free of the individual amino acids alanine, glutamic acid, glycine, isoleucine, valine, and proline, and are described with oral or food-carrier formats such as tablet, capsule, gel capsule, beverage, snack bar, and food composition.
The disclosure further describes sirtuin-pathway modulating compounds and sirtuin-pathway activating compounds defined by substituent-variable Markush formulas, with ring A and ring B selected from specified heteroaryl and heterocycle structures, together with solubilizing groups and optional substituent constraints. The description also provides explicit exclusions in which a listed compound is not included, and reports synergistic outcomes associated with increasing sirtuin-pathway and AMPK output, including improved insulin sensitivity, reduced inflammatory markers, increased thermogenesis and vasodilation, and increases in irisin and associated adipose browning markers.
Claims Coverage
The provided claim content identifies two overlapping inventive themes: one independent claim defines a composition with quantitative ingredient requirements, exclusion of specified amino acids, and specified oral or food-formulation formats; separate claim content is directed to sirtuin-pathway modulating and activating compounds defined by substituent-variable Markush formulas. Dependent claims refine the composition with additional quantitative constraints and selected ingredient embodiments.
Synergistic leucine metabolites with anti-diabetic agent composition
A composition comprising at least 500 mg of leucine and/or at least 200 mg of one or more metabolites thereof, wherein the one or more leucine metabolites are selected from keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and at least 100 mg of an anti-diabetic agent selected from a dipeptidyl peptidase (DPP) inhibitor and biguanide.
Substantially free of specified individual amino acids
The composition is substantially free of the individual amino acids alanine, glutamic acid, glycine, isoleucine, valine, and proline.
Oral/food-formulation presentation as tablet, beverage, or snack bar
The composition is formulated as a tablet, capsule, gel capsule, beverage, snack bar or a food composition.
Sirtuin-pathway modulating compounds with Markush formulas
Sirtuin-pathway modulating compounds and sirtuin-pathway activating compounds are defined by substituent-variable formulas in which ring A and ring B are selected from specified heteroaryl and heterocycle structures, with solubilizing groups and optional substituent constraints.
Explicit exclusions within compound definitions
The disclosure incorporates explicit exclusions in which a listed compound is not included.
Selected quantitative refinements in dependent coverage
Dependent coverage refines the composition by specifying an anti-diabetic amount range, a molar ratio requirement of (a) to (b) greater than about 5, and narrowing the DPP inhibitor to a selected list of compounds.
Across the provided claim text, the inventive coverage is anchored by a defined composition containing leucine and/or specific leucine metabolites at minimum amounts together with at least 100 mg of a DPP inhibitor or biguanide, exclusion of specified amino acids, and formulation in specified formats, while separate claim content covers sirtuin-pathway modulating and activating compounds defined by Markush formulas and explicit exclusions. Dependent claims further narrow the composition with additional quantitative constraints and selected anti-diabetic embodiments.
Stated Advantages
Modulates metabolic pathways through synergistic combinations that increase sirtuin-pathway output.
Induces fatty acid oxidation and mitochondrial biogenesis.
Improves insulin sensitivity and glucose uptake.
Alters inflammation markers.
Provides endpoints related to vasodilation and body temperature.
Promotes fat browning measures including UCP1 and related markers.
Potentiates anti-diabetic agents, including biguanides such as metformin.
Increasing sirtuin-pathway and AMPK output.
Enhancing mitochondrial biogenesis.
Enhancing fatty-acid oxidation.
Reducing inflammatory markers.
Increasing thermogenesis.
Increasing vasodilation.
Increasing irisin and associated adipose browning markers.
Documented Applications
Compositions and methods for treating or addressing metabolic disorders with physiological outcomes including insulin sensitivity, glucose uptake, inflammation markers, vasodilation/body temperature, and fat browning.
Use with anti-diabetic agents to potentiate anti-diabetic effects, including combinations involving biguanides such as metformin.
Oral administration as a formulation in multiple food and consumption formats, including beverages and snack bars.
Use in diet-induced obese or diabetic contexts is described through documented example outcomes, including insulin-sensitivity, inflammatory, adiposity, irisin/FNDC5, and adipose browning marker changes.
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