READ: Natural Activators of PPAR gamma: Its Role in Weight Gain, Inflammation.

PPAR is a protein that binds to DNA to increase gene expression i.e. to produce other important proteins.  There are three types: alpha, beta/delta, and gamma.

PPAR gamma can be activated in various cells, but it's most significant in fat cells/adipose tissue, followed by a colon, then kidney, then liver cells.

The Good

PPAR gamma (PPARy) most significantly increases insulin sensitivity and insulin secretion, which decreases blood glucose. (R) PPARs are generally  anti-inflammatory and block inflammation (MAPK, NF-kappaB, and others).

 PPARs produce an immune profile more similar to Th2 dominance. It's not surprising then that PPAR gamma activation is one mechanism by which mice can live longer (and maybe people). (R)

PPARy increases FGF-21 .   FGF-21 has been shown to benefit insulin sensitivity, blood glucose, cholesterol profile and decrease body weight in obese mice and diabetic monkeys, without increased cancer or other side effects. (R)

FGF-21 leads to increased energy expenditure, fat utilization, and excretion. (R) PPARs also cause the browning of white fat (good), which should help combat obesity .

Even though PPAR gamma increases FGF-21, which in turn increases energy expenditure, obese people have higher levels of FGF-21 . (R) This is simply because in the modern environment we just eat way too much for the amount of exercise we do.

PPAR gamma decreases inflammation in your heart and reduces cholesterol. (R) PPAR gamma has also been shown to reduce blood pressure in rats bred to have high blood pressure. (R)

Through these mechanisms, it's believed that it decreases heart disease.  (R) Diseases such as Multiple sclerosis and Alzheimer are associated with lower PPARgamma . (R) PPAR gamma decreases inflammation and can help IBD (Crohn's, colitis). (R)

PPAR gamma plays a relatively large role in colon cells. PPAR gamma increases ApoE (R), which 25% of the population have lower levels of and is implicated in Alzheimer's.

 ApoE is an anti-inflammatory, anti-oxidant and junk removal protein.  It also lowers cholesterol. PPAR gamma increases PON1 (R), which is an antioxidant and protects your heart.  It's important for handling pesticides.

The Bad

PPAR gamma can cause weight gain in some ways, even though it decreases it in other ways.  Overall, it seems to promote more weight gain, whereas PPAR alpha seems to promote more weight loss.

PPAR gamma can cause an increase in weight by increasing food intake, the production of fat cells and also makes fat cells bigger by increasing the uptake of fat and glucose in these cells. (R)

When mice are bred without PPAR gamma , they don't get fat on a high fat diet. (R) However, PPARs also cause weight loss by increasing energy expenditure and the browning of white fat. My guess is that whether you gain or lose weight will depend on your caloric intake and other factors.

CLA is a popular weight loss supplement and it inhibits PPAR gamma (R).  Berberine is also a popular weight loss supplement and it also inhibits PPAR gamma . In cancer cells, PPAR gamma has been shown to be involved in tumor growth. (R)

Activation, in general, could theoretically increase your risk for cancer. However, that's not always the case.  Honokiol is a supplement that increases PPARy in fat cells but decreases it in some cancer cells.  Also, it reduces weight gain in diabetes and doesn't increase fat cells. (R, R2, R3)  So we see substances can modify PPARy differently.

PPARs are not good for bone density.  They increase bone destroying cells (osteoclasts) and decrease bone-producing cells (osteoblasts). PPARs increase sodium and fluid retention. On the skin,  PPAR gamma increases sebum, which leads to acne. (R)

Indicators of low PPARs:

• You are thin and never tried to be thin,
• Have issues with  Th1 dominance (PPARy blocks IFNy),
• Have high inflammation. Cytokines like  TNF  and  IL-1  decrease PPARy and PPARy also decreases inflammation.  (R)  Check your inflammation: Th1/Th2/Th17 dominance.
• Have low fasting insulin (mine was below 2) (PPARs increase insulin),
• You have an HBA1C that's not low even though you eat REALLY healthy (no sugar).  PPARs lower blood glucose.
• Low  Adiponectin (PPAR gamma increases adiponectin) (R)
• High TGFb  (R) (PPARy lowers TGF).
• High  IGF-1 (R)

Indicators of normal PPARs:

• You are capable of gaining weight ,
• You're hungry often,
• Don't have chronic inflammation,
• You have high fasting insulin ,
• You're  Th2 dominant.  PPARy shifts you to a Th2 profile.

     From NCBI Gene: Familial partial lipodystrophy 3ObesityDiabetes mellitus type 2Carotid intimal medial thickness 1From UniProt: Glioma 1 (GLM1): Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. [MIM:137800] Obesity (OBESITY): A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. [MIM:601665] Lipodystrophy, familial partial, 3 (FPLD3): A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. [MIM:604367] Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer.

     From NCBI Gene: This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma . The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2008] From UniProt: Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels.

The following transcription factors affect gene expression:

• Egr-1
• CREB
• AP-1
• c-Jun
• deltaCREB
• C/EBPbeta
• C/EBPalpha
• FOXO1a
• FOXO1
• NF-AT3

Tissue specificity:

Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary.

Enzyme Regulation:

PDPK1 activates its transcriptional activity independently of its kinase activity.

Molecular Function:

• Core Promoter Sequence-Specific Dna Binding
• Dna Binding
• Chromatin Binding
• Transcription Factor Activity, Sequence-Specific Dna Binding
• Steroid Hormone Receptor Activity
• Rna Polymerase Ii Transcription Factor Activity, Ligand-Activated Sequence-Specific Dna Binding
• Prostaglandin Receptor Activity
• Transcription Factor Binding
• Drug Binding
• Zinc Ion Binding
• Enzyme Binding
• Ligand-Dependent Nuclear Receptor Transcription Coactivator Activity
• Activating Transcription Factor Binding
• Identical Protein Binding
• Transcription Regulatory Region Dna Binding
• Retinoid X Receptor Binding
• Arachidonic Acid Binding
• Alpha-Actinin Binding

Biological Processes:

• Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
• Placenta Development
• Negative Regulation Of Acute Inflammatory Response
• Transcription Initiation From Rna Polymerase Ii Promoter
• Lipid Metabolic Process
• Activation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Process
• Signal Transduction
• Heart Development
• Response To Nutrient
• Regulation Of Blood Pressure
• Response To Cold
• Response To Mechanical Stimulus
• Macrophage Derived Foam Cell Differentiation
• Negative Regulation Of Macrophage Derived Foam Cell Differentiation
• Negative Regulation Of Receptor Biosynthetic Process
• Negative Regulation Of Cholesterol Storage
• Negative Regulation Of Sequestering Of Triglyceride
• Long-Chain Fatty Acid Transport
• Fatty Acid Oxidation
• Monocyte Differentiation
• Negative Regulation Of Cell Growth
• Epithelial Cell Differentiation
• Response To Caffeine
• Animal Organ Regeneration
• Response To Retinoic Acid
• Cellular Response To Insulin Stimulus
• Negative Regulation Of Collagen Biosynthetic Process
• Response To Vitamin A
• Response To Lipid
• Peroxisome Proliferator Activated Receptor Signaling Pathway
• Response To Immobilization Stress
• Glucose Homeostasis
• Response To Starvation
• Regulation Of Circadian Rhythm
• Lipoprotein Transport
• Response To Estrogen
• Innate Immune Response
• Cell Fate Commitment
• Positive Regulation Of Fat Cell Differentiation
• Low-Density Lipoprotein Particle Receptor Biosynthetic Process
• Negative Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Positive Regulation Of Fatty Acid Oxidation
• Cell Maturation
• Rhythmic Process
• Negative Regulation Of Smooth Muscle Cell Proliferation
• Positive Regulation Of Oligodendrocyte Differentiation
• White Fat Cell Differentiation
• Positive Regulation Of Sequence-Specific Dna Binding Transcription Factor Activity
• Negative Regulation Of Telomerase Activity
• Lipid Homeostasis
• Response To Low-Density Lipoprotein Particle
• Positive Regulation Of Phagocytosis, Engulfment
• Negative Regulation Of Interferon-Gamma-Mediated Signaling Pathway
• Regulation Of Cholesterol Transporter Activity
• Regulation Of Transcription Involved In Cell Fate Commitment
• Cellular Response To Retinoic Acid
• Cellular Response To Vitamin E
• Cellular Response To Prostaglandin E Stimulus
• Cellular Response To Hyperoxia
• Response To Metformin
• Negative Regulation Of Pancreatic Stellate Cell Proliferation

Drug Bank:

• Icosapent
• Mesalazine
• Bezafibrate
• Ibuprofen
• Indomethacin
• Mitiglinide
• Nateglinide
• Pioglitazone
• Rosiglitazone
• Sulfasalazine
• Telmisartan
• Balsalazide
• Glipizide
• Repaglinide