Peroxisome proliferation activator receptors (PPARs) belongtothenuclearhormonereceptorsuperfamilythatalsoincludessteroidhormonereceptorsandthyroidhormonereceptors.PPARsheterodimerizewiththeretinoid X receptors (RXRs). Unlikesteroidandthyroidhormonereceptors,PPARsbindtoligandsinthemicromolarrange(i.e.,withloweraffinity).PPARsbindsaturatedandunsaturatedfattyacidsaswellasnaturalandsyntheticprostanoids.PPARγ ishighlyexpressedinadiposetissueandatalowerlevelinskeletalmuscleandliver.Itsnaturalligandsincludeseveralpolyunsaturatedfattyacids.PPARγ regulatesgenesthatpromotefatstorage.ItalsosynergizeswithSREBP1Ctopromotedifferentiationofadipocytesfrompreadipocytes.Tissue-specificknockoutofPPARγ inmiceandPPARγ-dominantnegativemutationsinhumansgiverisetolipodystrophy (i.e.,lackofwhiteadiposetissue),whichleadstodepositsofTGinmuscleandliver(calledsteatosis),insulinresistance,diabetes,andhypertension.
referred to as an adipocytokine. Circulating levels of leptin have a direct relationship with adiposity and nutritional status. Leptin output is increased by insulin, which prepares the body for correct partitioning of incoming nutrients. Leptin is inhibited by fasting and weight loss and by lipolytic signals (e.g., increased cAMP and β3-agonists).
Diet-induced obesity, advanced age, and T2DM are associated with leptin resistance. Thus mechanisms that turn off leptin signaling are potential therapeutic targets.
The amount of energy stored by an individual is determined by caloric intake and calories expended as energy per day. In many individuals, input and output are in balance, so weight remains relatively constant. However, the abundance of inexpensive high-fat, high-carbohydrate food, along with more sedentary lifestyles, is currently contributing to a pandemic of obesity and the pathological sequelae of obesity, including T2DM and cardiovascular disease.
The preponderance of stored energy consists of fat, and individuals vary greatly in the amount and percentage
Thethiazolidinediones areexogenousligandsforPPARγ.Althoughtheypromoteweightgain,moderatelevelsofthiazolidinedionessignificantlyimproveinsulinsensitivity.PPARγ alsostimulatessecretionofadiponectin, whichpromotesoxidationoflipidsinmuscleandfatandtherebyimprovesinsulinsensitivity.PPARα isabundantlyexpressedinliverandtoalesserextentinskeletalandcardiacmuscleandkidney.PPARα promotesuptakeandoxidationofFFAs.ThusPPARα isanantisteatoticmolecule.Thefibrates areexogenousligandsofPPARα andareusedtoreduceTGdepositsinmuscleandliver,therebyimprovinginsulinsensitivity.Athirdmember,PPARδ, similarlypromotesfattyacidoxidationinadiposeandmuscletissue.PPARδ promotesdevelopmentofslow-twitchoxidativemusclefibersandincreasesmusclestamina.PPARδ hasapositiveeffectonlipoproteinmetabolismbyincreasingproductionofApoAapoproteinsandthenumberofHDLparticles.