Compositions for treating or preventing obesity and insulin resistance disorders

Abstract

Provided herein are methods and compositions for modulating the activity or level of a sirtuin, thereby treating or preventing obesity or an insulin resistance disorder, such as diabetes in a subject. Exemplary methods comprise contacting a cell with a sirtuin activating compound or an inhibitory compound to thereby increase or decrease fat accumulation, respectively.

1 .- 12 . (canceled) 
     
     
         13 . A method for promoting weight gain in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that reduces the activity or protein level of a sirtuin in a cell. 
     
     
         14 . The method of  claim 13 , wherein the agent is a non-naturally occurring sirtuin-inhibitory compound, or prodrug thereof. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 14 , wherein the non-naturally occurring sirtuin-inhibitory compound or prodrug thereof is nicotinamide. 
     
     
         17 . The method of  claim 13 , further comprising administering to the subject a second agent. 
     
     
         18 . The method of  claim 17 , wherein the second agent is a weight gain-promoting agent. 
     
     
         19 .- 20 . (canceled) 
     
     
         21 . The method of  claim 13 , wherein the subject a human. 
     
     
         22 .- 29 . (canceled) 
     
     
         30 . The method of  claim 13 , wherein the sirtuin is SIRT1. 
     
     
         31 . The method of  claim 13 , wherein the subject has cachexia or is likely to develop cachexia. 
     
     
         32 . The method of  claim 13 , further comprising monitoring the activation of a sirtuin in adipose tissue of the subject. 
     
     
         33 . The method of  claim 13 , wherein the method further comprises decreasing or inhibiting the activity and/or protein level of 5′-AMP-activated protein kinase (AMPK). 
     
     
         34 . The method of  claim 17 , wherein the second agent (i) decreases the activity and/or protein level of a sirtuin; or (ii) decreases the activity and/or protein level of AMPK. 
     
     
         35 . The method of  claim 18 , wherein the weight gain-promoting agent is: a beta blocker, an alpha blocker, insulin, sulfonylurea, thiazolidinedione, meglitinide, nateglinide, repaglinide, lithium carbonate, valproic acid, carbamazepine, an antidepressant, a monoamine-oxidase inhibitor, a selective serotonin reuptake inhibitor, bupropion, paroxetine, mirtazapine, chlorpromazine, thiothixene, a steroid, a contraceptive, testosterone, or Megestrol. 
     
     
         36 . A method for stimulating fat accumulation in a cell, comprising contacting the cell with an agent that reduces the activity or protein level of a sirtuin in the cell. 
     
     
         37 . The method of  claim 36 , wherein the agent is a non-naturally occurring sirtuin-inhibitory compound or prodrug thereof. 
     
     
         38 . The method of  claim 37 , wherein the non-naturally occurring sirtuin-inhibitory compound or prodrug thereof is nicotinamide. 
     
     
         39 . The method of  claim 36 , further comprising contacting the cell with a second agent. 
     
     
         40 . The method of  claim 39 , wherein the second agent (i) decreases the activity and/or protein level of a sirtuin; (ii) decreases the activity and/or protein level of 5′-AMP-activated protein kinase (AMPK); or (iii) is a weight gain-promoting agent. 
     
     
         41 . The method of  claim 14 , wherein the non-naturally occurring sirtuin-inhibitory compound or prodrug thereof is: suranim, NF023, NF279, Trolox (6-hydroxy-2,5,7,8,tetramethylchroman-2-carboxylic acid), (−)-epigallocatechin (hydroxy on sites 3,5,7,3′,4′,5′), (−)-epigallocatechin (hydroxy on sites 3,5,7,3′,4′,5′), (−)-epigallocatechin gallate (Hydroxy sites 5,7,3′,4′,5′ and gallate ester on 3), cyanidin choloride (3,5,7,3′,4′-pentahydroxyflavylium chloride), delphinidin chloride (3,5,7,3′,4′,5′-hexahydroxyflavylium chloride), myricetin (cannabiscetin; 3,5,7,3′,4′,5′-hexahydroxyflavone), 3,7,3′,4′,5′-pentahydroxyflavone, gossypetin (3,5,7,8,3′,4′-hexahydroxyflavone), sirtinol, or splitomicin. 
     
     
         42 . The method of  claim 37 , wherein the non-naturally occurring sirtuin-inhibitory compound or prodrug thereof is: suranim, NF023, NF279, Trolox (6-hydroxy-2,5,7,8,tetramethylchroman-2-carboxylic acid), (−)-epigallocatechin (hydroxy on sites 3,5,7,3′,4′,5′), (−)-epigallocatechin (hydroxy on sites 3,5,7,3′,4′,5′), (−)-epigallocatechin gallate (Hydroxy sites 5,7,3′,4′,5′ and gallate ester on 3), cyanidin choloride (3,5,7,3′,4′-pentahydroxyflavylium chloride), delphinidin chloride (3,5,7,3′,4′,5′-hexahydroxyflavylium chloride), myricetin (cannabiscetin; 3,5,7,3′,4′,5′-hexahydroxyflavone), 3,7,3′,4′,5′-pentahydroxyflavone, gossypetin (3,5,7,8,3′,4′-hexahydroxyflavone), sirtinol, or splitomicin.