Methods for promoting lipolysis and oxidation in liver and adipose tissue using catestatin
Inventors
Mahata, Sushil K. • Bandyopadhyay, Gautam K.
Assignees
Office of General Counsel of VA • University of California San Diego UCSD
Publication Number
US-9572862-B2
Publication Date
2017-02-21
Expiration Date
2033-04-01
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Abstract
The invention provides methods for treating obesity in a subject comprising administering an effective amount of catestatin (CST) or its equivalent to a subject afflicted with obesity so as to maintain an effective amount of circulating catestatin in the subject to promote lipolysis and oxidation of released fatty acids in both liver and adipose tissue, thereby, reducing adipose tissue weight and hence treating obesity in the afflicted subject.
Core Innovation
The invention provides methods for treating obesity in subjects by administering an effective amount of catestatin (CST) or its equivalent to maintain circulating CST levels that promote lipolysis and oxidation of released fatty acids in both liver and adipose tissue, thereby reducing adipose tissue weight and treating obesity. It further discloses the use of CST to reverse leptin resistance in brain and peripheral tissues by decreasing hyperleptinemia and restoring leptin sensitivity. Additionally, the invention offers methods to decrease plasma triglyceride levels, reduce hypertension associated with obesity, enhance lipid metabolism, and improve insulin clearance and sensitivity in subjects with insulin resistance or diabetes.
The problem addressed by the invention arises from the complexity of obesity pathology, including β-adrenergic receptor desensitization and leptin receptor (Ob-R) resistance due to chronic hyperleptinemia, which impair lipolysis and fatty acid oxidation. Chromogranin A knockout (Chga-KO) mice lacking endogenous CST show increased adiposity despite high catecholamine and leptin levels due to leptin receptor desensitization. Existing therapies fail to adequately restore the balance between these hormonal signals and their receptors to promote lipid mobilization and oxidation effectively. The invention solves this by administering CST or equivalents to normalize catecholamine and leptin signaling, enhancing lipolysis, fatty acid oxidation, and restoring receptor sensitivity, thereby reducing obesity.
Claims Coverage
The patent includes 11 claims with one independent claim describing a method for treating obesity using CST or its equivalents and other dependent claims elaborating on specific embodiments and variations.
Method for treating obesity using catestatin and its equivalents
Administering an amount of catestatin (CST) or CST equivalents, including retro-inverso versions and variant sequences (such as SEQ ID NOs: 2, 3, 4, 55, 56, 57) to maintain effective circulating CST levels to promote lipolysis and fatty acid oxidation in liver and adipose tissue, thereby reducing adipose tissue mass and treating obesity in an obese subject.
Administration routes and obesity types
Administering CST or equivalents via various routes including enteral, buccal, intraperitoneal, inhalation, intravenous, subcutaneous, or intramuscular to treat obesity, including diet-induced obesity and obesity associated with reduced circulating CST or β-adrenergic receptor sensitivity.
Leptin receptor targeting by catestatin or equivalents
CST or equivalents function as ligands for the leptin receptor (Ob-R), acting as partial agonists with leptin-like activity, competing with leptin for binding, specifically through the Ig-like domain of Ob-R, thereby modulating leptin receptor signaling.
Specific peptide sequences for catestatin equivalents
CST or equivalents comprise specific peptide sequences selected from a broad list including human CST sequences and variants (e.g., SEQ ID NOs:1-4, 55-57, 12-25), and corresponding sequences from various species (bovine, porcine, rat, mouse, monkey, etc.), and their retro-inverso peptides comprising D-amino acids with reversed amino-to-carboxyl sequences.
The claims cover methods of using CST and its structural variants, including retro-inverso peptides, administered via multiple routes to treat obesity by promoting lipolysis and fatty acid oxidation, leveraging CST's interaction with leptin receptors and adrenergic signaling to modulate metabolic pathways effectively.
Stated Advantages
Reduction of adipose tissue weight by promoting lipolysis and oxidation of fatty acids in liver and adipose tissue.
Restoration of leptin receptor sensitivity in brain and peripheral tissues by decreasing hyperleptinemia.
Decrease of plasma triglyceride levels in treated subjects.
Reduction of hypertension associated with obesity via lowering catecholamine and Neuropeptide Y levels.
Enhancement of therapeutic effectiveness of anti-diabetic drugs by reducing side effects such as weight gain and cardiovascular risks.
Ability to potentiate lipolytic effects through combination therapies targeting adrenergic receptors.
Provision of stable CST equivalents including retro-inverso peptides that may have improved bioavailability and prolonged activity.
Documented Applications
Treatment of obesity, including diet-induced obesity, by promoting lipolysis and fatty acid oxidation.
Reversal of leptin resistance in brain and peripheral tissues to restore leptin receptor sensitivity.
Reduction of plasma triglyceride levels in subjects.
Treatment of hypertension associated with obesity by reducing catecholamine and Neuropeptide Y levels.
Enhancement of anti-diabetic therapy by mitigating weight gain and cardiovascular risks associated with such drugs.
Improvement of insulin sensitivity and clearance in diabetic and insulin resistant subjects.
Combination therapies involving CST and adrenergic receptor agonists or antagonists to augment lipolysis.
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