Peroxisome proliferation activator receptors (PPARs) are part of the nuclear hormone receptor superfamily, which also includes steroid hormone receptors and thyroid hormone receptors. PPARs heterodimerize with the retinoid X receptors (RXRs). Unlike steroid and thyroid hormone receptors, PPARs have lower affinity and bind to ligands in the micromolar range. PPARs can bind both saturated and unsaturated fatty acids, as well as natural and synthetic prostanoids. PPARγ is highly expressed in adipose tissue and to a lesser extent in skeletal muscle and liver. Its natural ligands include several polyunsaturated fatty acids. PPARγ regulates genes that promote fat storage and works together with SREBP1C to promote the differentiation of adipocytes from preadipocytes. When PPARγ is specifically knocked out in mice or there are dominant negative mutations in humans, it leads to lipodystrophy (lack of white adipose tissue), which results in the accumulation of triglycerides in muscle and liver (known as steatosis), insulin resistance, diabetes, and hypertension. Leptin is referred to as an adipocytokine and its circulating levels are directly related to adiposity and nutritional status. Insulin increases leptin output, preparing the body for proper distribution of incoming nutrients. Fasting, weight loss, and lipolytic signals inhibit leptin production. Leptin resistance is associated with diet-induced obesity, advanced age, and type 2 diabetes mellitus. Therefore, mechanisms that regulate leptin signaling are potential targets for therapy. The amount of energy stored in an individual is determined by caloric intake and the calories expended per day. While many individuals have a balance between input and output, leading to relatively constant weight, the prevalence of affordable high-fat, high-carbohydrate food and sedentary lifestyles is currently contributing to a global obesity pandemic and its associated conditions, including type 2 diabetes mellitus and cardiovascular disease. The majority of stored energy in the body consists of fat, and the amount and percentage vary greatly among individuals. Thiazolidinediones are exogenous ligands for PPARγ. While they promote weight gain, moderate levels of thiazolidinediones significantly improve insulin sensitivity. PPARγ also stimulates the secretion of adiponectin, which enhances lipid oxidation in muscle and fat, thus improving insulin sensitivity. PPARα is abundantly expressed in the liver and to a lesser extent in skeletal and cardiac muscle and the kidney. PPARα promotes the uptake and oxidation of free fatty acids, making it an anti-steatotic molecule. Fibrates are exogenous ligands for PPARα and are used to reduce triglyceride deposits in muscle and liver, thereby improving insulin sensitivity. PPARδ, the third member, similarly promotes fatty acid oxidation in adipose and muscle tissue. PPARδ also promotes the development of slow-twitch oxidative muscle fibers and increases muscle endurance. Additionally, PPARδ has a positive effect on lipoprotein metabolism by increasing the production of ApoA apoproteins and the number of HDL particles.
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.