Up-Regulation of Peroxisome Proliferator-Activated Receptors (PPAR-α) and PPAR-γ Messenger Ribonucleic Acid Expression in the Liver in Murine Obesity: Troglitazone Induces Expression of PPAR-γ-Responsive Adipose Tissue-Specific Genes in the Liver of Obese Diabetic Mice**This work was supported by grants from the Research Service of the Department of Veterans Affairs (to C.G. and K.R.F.), NIH Grant DK-49448 (to C.G.), and Merck Research Laboratories (to L.H.T. and K.N.).

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agoutiexpression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-γ protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-γ.

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Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies

Planta Medica ◽

10.1055/a-0824-1316 ◽

2019 ◽

Vol 85 (05) ◽

pp. 412-423 ◽

Cited By ~ 5

Author(s):

Abraham Giacoman-Martínez ◽

Francisco Alarcón-Aguilar ◽

Alejandro Zamilpa ◽

Sergio Hidalgo-Figueroa ◽

Gabriel Navarrete-Vázquez ◽

...

Keyword(s):

Glucose Transporter ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Messenger Ribonucleic Acid ◽

Transporter Protein ◽

Agonist Action ◽

Fatty Acid Transporter ◽

Peroxisome Proliferator Activated Receptors ◽

Glucose Transporter Type 4 ◽

Dual Agonist

Abstract Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ/γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α-amyrin and lupeol. These molecules were subjected to molecular docking analysis. α-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ/γ dual agonist action.

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Effects of DHEA on metabolic and endocrine functions of adipose tissue

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0009 ◽

2013 ◽

Vol 14 (2) ◽

Cited By ~ 5

Author(s):

Joanna Karbowska ◽

Zdzislaw Kochan

Keyword(s):

Adipose Tissue ◽

Human Adipose Tissue ◽

Hormone Sensitive Lipase ◽

Peroxisome Proliferator ◽

Tissue Mass ◽

Triacylglycerol Hydrolysis ◽

Proliferation And Differentiation ◽

Hormone Sensitive ◽

Hormone Biosynthesis ◽

Peroxisome Proliferator Activated Receptors

AbstractDehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the major circulating adrenal steroids and serve as substrates for sex hormone biosynthesis. DHEA is effectively taken up by adipose tissue, where the concentrations of free DHEA are four to ten times higher than those found in the circulation. DHEA reduces adipose tissue mass and inhibits the proliferation and differentiation of adipocytes; it may also protect against obesity by lowering the activity of stearoyl-CoA desaturase 1 in fat cells. Recent studies demonstrate that DHEA stimulates triacylglycerol hydrolysis in adipose tissue by increasing the expression and activity of adipose triglyceride lipase and hormone-sensitive lipase, the key enzymes of lipolysis. DHEA has been shown to modulate insulin signaling pathways, enhance glucose uptake in adipocytes, and increase insulin sensitivity in patients with DHEA deficiency or abnormal glucose tolerance. Additionally, by suppressing the activity of 11β-hydroxysteroid dehydrogenase 1 in adipocytes, DHEA may promote intra-adipose inactivation of cortisol to cortisone. Several studies have demonstrated that DHEA may also regulate the expression and secretion of adipokines such as leptin, adiponectin, and resistin. The effects of DHEA on adipokine expression in adipose tissue are depot-specific, with visceral fat being the most responsive. The mechanisms underlying DHEA actions in adipose tissue are still unclear; however, they involve nuclear receptors such as androgen receptor and peroxisome proliferator-activated receptors γ and α. Because clinical trials investigating the effects of DHEA failed to yield consistent results, further studies are needed to clarify the role of DHEA in the regulation of human adipose tissue physiology.

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