INTRODUCTION:

In recent years it has become evident that the societies of the developed countries are at immense risk of diseases like pancreatic cancer which is most common and most deadly cancers with the incidence approaching mortality [1] and the so-called civilization diseases or X syndrome. In fact, the rise in the prevalence of specific endocrine-related diseases such as obesity and diabetes clearly suggests an importance of either environmental other factors responsible for them.

Reasons contributing to this lethality are the delayed diagnosis and the anatomic position and close relationships of the organ that precludes complete resection in many instances even in localized cases of pancreatic cancer. Nevertheless, the majority of patients that have been completely rejected recur. This fact attests for the presence of occult micro metastases in early stages and an intrinsic aggressiveness of pancreatic cancer. Despite advancements in the molecular biology of pancreatic cancer and discovery of key molecular lesions playing a part in the pathogenesis such as K-ras, p53, p16, and DPC4, this progress has not been translated in therapeutic results. In clinical practice, drugs used in pancreatic cancer such as gemcitabine,[2] combination regimen of 5-FU, Folinic acid, Irinotecan, and Oxaliplatin [3] are given in a nondiscriminatory way to all metastatic patients that can tolerate them.

Recently, several different transcriptional factors have been identified as regulators of the expression of a set of genes involved in glucose and lipid metabolism as well as pancreatic cancer. Among them, peroxisome proliferator- activated receptors (PPARs), belonging to the superfamily of nuclear receptors (NRs), have been shown to play a central role in the transcriptional control of genes encoding proteins involved in the above processes and expressed in several types of cancers among which gastrointestinal and pancreatic cancers. Three different human PPAR subtypes have been identified so far, designated as PPAR-γ (also known as PPAR-γ, or NUCI in humans, or FAAR in rodents), and PPAR-γ [3,4,5].

PPAR-γ is predominantly expressed in the liver and skeletal muscles, also higher expression observe in subset of pancreatic cancer[6,7]. It has been recognized to have higher expression of PPRA-γ in placenta and large intestine [8,9,67]. Nonetheless current conclusion have mixed up PPAR-β as an significant manager of energy spending as well as glucose and lipid metabolism [10,11,12,13]. Out of the 3 members of PPAR-γ is the most regularly intentional NR caught up in the organize of supremacy equilibrium and together lipid and glucose homeostasis [14,15,16]. This transcriptional thing is whispered to be a crucial manager of adipogenesis given that it is spoken principally in adipose tissue [31,32]. PPAR-γ forms a heterodimer multifaceted with retinoid X receptor-γ (RXRγ), which then binds to peroxisome proliferator response elements (PPREs) contained by the promoters of PPAR-γ-targeted genes [17,18,19]. The PPAR-γ RXRγ heterodimer may be activated by a range of ligands. Compared among traditional NRs such as estrogen receptors, PPAR-γ interacts with a wide spectrum of innate [20,21,22] and artificial [25,26,66] lipophilic ligands. The natural ligands comprise polyunsaturated fatty acids [20,21], prostaglandin (PG)J2 derivatives [21,22,66], and oxidized fatty acids [27,66,67]. Of the artificial ligands, thiazolidinediones (TZDs) are compounds that show evidence of high similarity to PPAR-γ and are utilized to augment insulin sympathy in diabetic patients [28,29,30,66,67]. This review summarizes current knowledge on the structure and physiological functions of PPARγ in case of Pancreatic cancer.

Figure: Domain structure of PPARs. PPARs contain the following functional regions: an N-terminal A/B domain with AF-1 (ligand--independent activation domain), a C domain with two zinc fingers (DNA-binding domain), a D domain (hinge domain), and a C-terminal E/F domain containing AF-2 (ligand-binding domain).

1. STRUCTURE OF THE PPARγ PROTEIN:

Notwithstanding four dissimilar mRNA subtypes, the PPARγ exists in two protein isoforms (elected hPPAR-γ1 and -γ2) consequential beginning different advertiser tradition and substitute splicing at the 5’ end of the genetic material. hPPAR-γ1, -γ3, and -γ4 mRNA provide rise to an indistinguishable protein produce, hPPAR-γ1 (477 aa), while hPPAR-γ2 mRNA encodes the hPPAR-γ2 protein with 30 further N-terminal amino acids (505 aa) encoded through the B exon. Similar to all NRs, PPARs contribute to a comparable modular configuration with functionally dissimilar domains called A/B (ligand- autonomous commencement domain), C (DNA binding domain), D (hinge domain), and E/F (ligand-binding domain – LBD) [31]. The N-terminal domain A/B has been comparatively healthy preserved throughout development. The leader portion of this domain is an α-helix section possessing a ligand-independent activating occupation (AF-1) [32]. It has been revealed that the hPPAR-γ2 isoform exhibits tenfold higher movement than hPPAR-γ1 in the occurrence of insulin in ligand-independent transcriptional commencement [32]. This data may involve dissimilar functions of the two isoforms that fluctuate only in their N-terminal. So far, the role of the supplementary 30 amino-acid residue at the N-terminus of the hPPAR-γ2 protein has not been explained. However, there are some hypotheses concerning this portion relating to its consequence on an augment in receptor movement [33]. Additionally, in the A/B domain is Ser-112 (also referred to as Ser-114 in the literature), which is question to phosphorylation [34]. Since intramolecular communique connecting the A/B and the LBD domains is compulsory for ligand binding, the phosphorylation at Ser-112 by mitogen-activated protein kinase (MAPK) disrupts interdomain statement, consequential in a decrease in ligand-binding resemblance [34]. Furthermore, the MAPK-dependent phosphorylation of this remainder in the hPPAR-γ2 protein inhibits its aptitude to encourage unambiguous gene appearance and the development of adipogenesis [35].

The C domain is the most preserved of all the purposeful domains [31]. It contains two zinc finger-like motifs that are accountable for binding of the receptor to the DNA advertiser of objective genes. Each of the zinc fingers is programmed by a disconnect exon (2 and 3). Further the zinc fingers present are amino-acid motives formative the acknowledgment of an inappropriate DNA succession which joints the receptor. Furthermore, a great division of the domain takes part in dimerization with any more NR, RXR. The fewer preserved domain D is treated slightly as a bendable pivot connecting the C and E/F domains [31]. This location is also a docking domain for cofactors. In calculation, it contains the nuclear localization indication, a progression documented by transporting proteins, which determines rearrangement of the synthesized protein starting the cytoplasm to the cell nucleus. Furthermore, several of the amino acids are concerned in the behavior of together close domains, principal to the dimerization and gratitude of the objective DNA progression. The biggest domain is the LBD (E/F domain) positioned at the C-terminus [36], and accountable for the compulsory of a unambiguous ligand and commencement of PPAR compulsory to PPREs in the object gene advertiser. The LBD contains a splinter called ligand--dependent commencement function 2 (AF-2), unavailable in the employment of PPAR cofactors to support the genetic material transcript processes [37].

The crystallographic agreement of the LBD of PPAR-γ uncovered common similarities to other NR structures [36, 38]. It has been firm so as to the unliganded LBD possesses a little β-sheet of four strands and 12 extremely preserved α-helices that are folded into three layers to generate a innermost hydrophobic ligand-binding compartment, approximately completely covered contained by the central part of these α-helices [36,38]. In adding up to the construction of a archetypal NR, the PPAR-γ LBD contains one supplementary α-helix among the β-strand and twist 3. The conformation of helix 12 is dangerous for transcriptional opening since noteworthy differences have been experimental in the position. Over the past several years, different ordinary and artificial PPAR-γ ligands, counting PPAR-γ agonists [39], PPAR-γ incomplete agonists [40], and PPAR-α/γ dual agonists [41], contain been investigated. Among the acknowledged endogenous PPAR-γ agonists are polyunsaturated full of fat acids (linoleic and arachidonic acids) [42,43], PG-related compounds resultant from nourishment or the metabolic alleyway (15d-PGJ2 and delta12-PGJ2) [44,45], and corroded fatty acids (9- and 13-HODE, 15-HETE) [46]. Since most of these normal compounds attach and make active PPAR-γ at micromolar concentrations [44,45], it is not clear whether their pertinent concentrations of this helix for agonist and antagonist-bound forms of the estrogen receptor [47]. A “mouse trap” replica of receptor commencement has therefore been projected. According to this replica, helix 12, containing the preserved AF-2 core, closes the ligand obligatory site in comeback to a ligand, ensuing in a transcriptionally full of life form of the receptor [48].

The freshly solved X-ray configuration of the PPAR- -γ/RXRα LBD heterodimer as a multipart with GW409544 and two LXXLL (L, leucine; X, any amino acid) peptides from steroid receptor coactivator open that the tart start group of the ligand GW409544 forms hydrogen bonds with whichever His- -323 (helix 5) or Tyr-473 (the AF2 helix) within PPAR-γ [41]. In addition, assessment of the structures of GW409544 bound to PPAR-α and PPAR-γ, along with mutational psychoanalysis of their LBDs, resulted in the recognition of the single amino acids which settle on ligand selectivity. These are Tyr-314 in PPAR-α and His-323 in PPAR-γ, which comprise part of the system of hydrogen-binding residues caught up in the commencement of PPAR during its acidic ligands [41].

It is remarkable that the classification of a major determinant of selectivity flanked by PPAR-α and PPAR-γ has provided the chance to intend new diabetes drugs. Over the past several years, various ordinary and imitation PPAR-γ ligands, counting PPAR-γ agonists [39], PPAR-γ incomplete agonists [40], and PPAR-α/γ dual agonists [41], have been investigated. Among the known endogenous PPAR-γ agonists are polyunsaturated fatty acids (linoleic and arachidonic acids) [42, 43], PG-related compounds derivative from sustenance or the metabolic alleyway (15d-PGJ2 and delta12-PGJ2) [44, 45], and oxidized oily acids (9- and 13-HODE, 15-HETE) [46]. Since nearly all of these innate compounds connect and trigger PPAR-γ at micromolar concentrations [44, 45], it is not clear whether their pertinent concentrations in the nuclei of objective cells are adequate for receptor commencement. Recent studies on physically pertinent endogenous adipogenic PPAR-γ ligands have revealed the existence of narrative hydrophobic ligands detailed to PPAR-γ, fleetingly generated in 3T3-L1 cells in answer to amplified cAMP throughout an early phase of adipogenesis [49]. These new data entail that the making of such ligand (not yet identified) is an imperative development upsetting the adipogenic course. The copied PPAR-γ agonists are thought to be factors influential adipocyte discrimination as well as budding antidiabetic drugs [39, 50, 51]. Compounds such as TZDs are used clinically as insulin sensitizers [52]. They make active PPAR-γ and diminish insulin confrontation and glucose height in the serum of patients with type 2 diabetes [52].

A lot of drugs belonging to the TZD class display elevated selectivity for PPAR-γ and negligible or no movement near other subtypes-α and - β [53]. For example, troglitazone (Rezulin) is a very detailed high- affinity PPAR-γ ligand with a Kd of 30–700 nM [39]. However, despite important antidiabetic actions, TZDs reason numerous side effects, such as augmented adiposity, oedema, and cardiac hypertrophy. From the healing point of outlook, perfection of the pharmacological profiles of PPAR-γ ligands is exceedingly obligatory. Therefore, substitute advance, relying on the naming of a fractional agonist, was urbanized. It was freshly reported that a PPAR-γ fractional agonist parallel to LSN862, i.e. (S)-2 methoxy-3-{4-[5-(4-phenoxy) pent -1-ynyl] phenyl}-propionic acid, has better antidiabetic commotion and weaker side effects than the TZDs [54]. Additional freshly, a original relatives of PPAR-γ fractional agonists (pyrazol-5-yl benzenesulfonamide derivatives) with moreover lofty effectiveness or specificity in vitro or glucose-lowering effectiveness in vivo has been recognized [40]. fascinatingly, the X-ray structures of the PPAR-γ-ligand complexes exposed a lack of hydrogen bonds flanked by them. This is in pointed difference to PPAR-γ agonists distribution a common compulsory manner in which the acidic cranium groups form a network of hydrogen communications with His-323, His-449, and Tyr-473 within the ligand required compartment [41]. Additional molecular studies are obligatory to comprehend how PPAR-γ unfinished agonists change transcriptional motion during the employment of coactivator and corepressor proteins.

2. PPARγ in Pancreatic Cancer:

PPARγ has been investigated inmultiple preclinical studies in pancreatic tumor. PPARγ commencement by troglitazone summary the propagation of pancreatic cancer cell appearance in vitro and had an preservative consequence with 9-cis-retinoic acid, a ligand for RXRα [55]. Cyclin D1 mRNA and protein appearance was decreased after troglitazone dealing. An additional in vitro study of some pancreatic cell outline showed uneven propagation embarrassment and cell sequence seize in G1 phase before troglitazone handling [56]. Notwithstanding PPARγ appearance, several pancreatic cell shape were troglitazone unwilling. CDK inhibitor p21 was upregulated perhaps due to mRNA stabilization. Troglitazone management also promoted discrimination of pancreatic cancer cells with canal configuration and rigid junctions pattern [56]. The expected PPARγ ligand 15d-PGJ2-induced apoptosis in a pancreatic cancer cubicle line with assistant commencement of MAPKs JNK, p38, and ERK [57]. Apoptosis was reliant on MAPK p38, as the pharmacologic embarrassment of this kinase prior to 15d- PGJ2 handling prohibited apoptosis beginning. In dissimilarity pharmacologic shyness of the ERK limb of MAPKs had it appears that no position in PPARγ-induced apoptosis following 15d-PGJ2 conduct in this cell line [57]. Troglitazone treatment of pancreatic cancer cell lines reserved their invasiveness in vitro and induced a rounding of cells that was reversible upon taking away of the treatment from the society [58]. In another study a dissimilar thiazolidinedione, ciglitazone, and 15d-PGJ2 repressed pancreatic cancer cell assault [59]. This consequence was PPARγ needy as it was annulled by a PPARγ antagonist or adenoviral transfection of cells with a dominant-negative PPARγ and appeared to be at slightest partly mediated by mechanism of the uPA (urokinase-type Plasminogen Activator) system. Other investigators reported an increase of PAI-1 (Plasminogen Activator Inhibitor 1) and a diminish in cell assault in pancreatic cancer cell lines treated with rosiglitazone or pioglitazone but these property seemed to be sovereign of PPARγ foundation for the reason that they were experimental still in cell lines to did not articulate the nuclear receptor [60]. The same team of investigators showed that rosiglitazone- or pioglitazone-induced reserve of anchorage-independent enlargement of pancreatic carcinoma cells was PPARγ reliant [61]. PPARγ ligands also induced a more differentiated morphology and delineation markers Carbonic Anhydrase II (CA II) and cytokeratin 7, in addition to CDK inhibitors p21 and p27 in these cells, but they had no apoptosis introduction upshot [61]. Appearance of PPARγ in pancreatic cell lines needs to be accompanied by transcriptional functionality in sort to be talented to intercede shyness upshot; In a study of quite a few cancer cell appearance amid which were pancreatic cell appearance KMP-2 and BxPC3, only KMP-2 can be repressed by different thiazolidinediones [62]. This cell line was expressing a purposeful PPARγ while in BxPC3 cells, PPARγ, even though vigorous appearance was not efficient in a transactivation analyze [62]. In an in vivo study in Syrian blond hamsters, pioglitazone feeding summary the numbers of N-nitrosobis (2- oxopropyl) amine (BOP)induced pancreatic cancer [63]. These hamsters, in dissimilarity to additional rodents, have low lipoprotein lipase (LPL) movement, increase hypertriglyceridemia, and hypercholesterolemia and are predominantly receptive to BOP carcinogenesis. Pioglitazone, in equivalent with decrease of pancreatic cancer expansion in these animals, condensed the occurrence of cholangiocarcinoma and induced LPL expression [63].

In an additional in vivo study, rosiglitazone conduct summary human being pancreatic xenograft tumor size in nude mice and decreased microvessel compactness evaluated by endothelial cell discoloration for collagen IV [64]. Pharmacologic self-consciousness of PPARγ by detailed inhibitor T0070907 suddenly also concentrated pancreatic cancer cells relocation in vitro and metastasis configuration in an SCID mouse xenograft replica in vivo [65]. T0070907 handling induced membranous p120 catenin growth and GTPases Cdc42 and Rac-1 reserve, proceedings that would be unsurprising to donate to cell union stabilization and motility lessening. In general, these statistics quarrel for a position of PPARγ in pancreatic cancer cell production, demarcation and invasiveness. The picture decorated from obtainable investigational confirmation speaks for a responsibility of PPARγ commencement in suggest cell sequence detain and additional differentiated phenotype and in plummeting cell invasiveness. Nevertheless, nearly all figures approach beginning in vitro studies and have boundaries. One of these boundaries relates to the utilize of pharmacologic activators to suppose property of PPARγ opening on cellular properties. Thiazolidinediones for example, encompass properties that are PPARγ sovereign production the assessment of PPARγ donation chiefly tricky. Use of pancreas beleaguered PPARγ put to sleep models in vivo or PPARγ RNA prying in vitro as an substitute or in totaling to pharmacologic activators would help resolving these troubles. Other discrepancies may recount to mechanical issues, antibodies worn, and cell lines classification. For example, a compartment procession shabby in one of the above discussed studies [60] and reported not to articulate PPARγ and thus causative to the disagreement that personal property observe were PPARγ autonomous was originate to vigorously communicate the nuclear receptor in a different learn [65]. In adding together, extra conflicting effectsmay trunk beginning differences in the cellular situation that could alter the personal property of PPARγ unswervingly or circuitously, for illustration, from first to last phosphorylation of the receptor or ease of use of cofactors.

3. Effect of TZDs on Adipokines:

Considering as adipose tissue is also an endocrine appendage, numerous adipocyte -unseen molecules, counting TNF-α, leptin, resisting (also known as FIZZ3, mXCP4, hXCP1), adiponectine, and interleukin (IL)-6, have been concerned in the guideline of insulin sympathy. Numerous studies encompass paying attention on influential the function of TNF-α in the pathogenesis of insulin fighting in type 2 diabetes. It has been conventional in numerous mammal models of chubbiness that the levels of TNF-α mRNA are augmented in adipose tissue [103] and, moreover, the neutralization of TNF-α in heavy rats causes a noteworthy augment in the unimportant uptake of glucose in rejoinder to insulin [105]. In calculation, quite a lot of lines of confirmation on or after studies on living thing models have supported the opinion of a decisive role for TNF-α in obesity-related insulin struggle in vivo [68, 69, 104]. TZDs have momentous possessions on the motion of this cytokine. It has been experiential that troglitazone management of rats infused with TNF-α prevents the orientation of insulin confrontation [70], whereas pioglitazone blocks TNF-α-mediated property, as well as decreased glucose uptake and LPL mRNA plane in adipocytes from a TNF-α-overexpression mice model [71]. TZDs have also been concerned in the parameter of leptin appearance either in cultivated adipose cells or in vivo, causing a decrease of leptin mRNA and protein levels [72, 73]. However, there are some contrasting data pertaining to the role of leptin in human insulin fighting in vivo. Muller et al. [74] have shown that leptin impairs the metabolic accomplishment of insulin in cut off rat adipocytes, while other answer suppose that leptin may also augment insulin understanding [75, 76]. Resistin was acknowledged as an adipocyte -concealed factor answerable for insulin confrontation in both educated cells and hereditarily or diet-induced mouse chubbiness rats [77, 78]. It has been not compulsory that this protein may contribute in a instrument by which stoutness is associated to insulin confrontation and diabetes, since its echelon is decreased by rosiglitazone in 3T3-L1 adipocytes and in WAT of mice fed a high-fat diet [78, 79, 66]. Of fastidious notice is that there are conflicting mammal answer representative augmented [78, 79, 66] or decreased [80, 81 82] levels of resistin in corpulence and moreover decreased [78, 79, 83, 84] or augmented [85, 86] levels by TZDs. Additionally, together the appearance and emission of resistin in 3T3-L1 adipocytes is repressed by TNF-α, which causes insulin confrontation [83, 87]. Additionally, a number of human being studies have bare a lack of connection stuck between chubbiness or insulin confrontation and serum resistin concentrations in humans [88, 89], implying that resistin is not a master hormone between obesity to diabetes. Furthermore, it has freshly been shown that resistin is fashioned principally by monocytes and macrophages in humans [90]. Thus, the significance of resistin in the directive of insulin sympathy remnants uncertain and additional studies are necessary to determine this matter. Surrounded by the adipokines, much concentration has been paid to the position of adiponectin, which is induced through adipocyte separation [91], in insulin confrontation. It has been recognized that the plasma concentrations of adiponectin in overweight subjects are considerably inferior than in non-obese subjects [92] and so as to these summary concentrations are connected with insulin confrontation in dissimilar ethnic groups [93]. TZD behavior may cause an augment in adiponectin levels in subjects with standard or impaired glucose receiving, and in patients with type 2 diabetes [94, 95, 96, 97]. These consequences are also supported by Yu et al. [98], who established, based on augmented adiponectin levels in normal rats, bend subjects, and non responders, that adiponectin by yourself is not able to suggest TZD- induced insulin compassion. Additionally, an opposite connection between adiponectin and insulin levels has been originate [98]. Therefore it is evident that the chronic hyper-insulinemia associated with insulin-resistance can guide to down guideline of adiponectin concentration. It is remarkable that adiponectin can augment insulin achievement in influence and liver, even though the machinery is unmoving uncertain. Adiponectin has also been institute to develop insulin encouraged tyrosine phosphorylation of the insulin receptor in emaciated muscle [66, 99] and to decrease hepatic appearance of the glucogenic enzymes, PEPCK, and glucose-6-phosphatase [66, 100]. IL-6 is one additional particle concealed from adipose tissue with signaling probable. It has been established that adipose tissue is equal to exude a great quantity of IL-6, by means of an augmented manufacture in stout subjects [66, 101], and present is constructive connection stuck between circulating IL-6 levels and insulin confrontation [66, 102]. However, the role of IL-6 in the molecular instrument concerned in obesity- connected insulin confrontation is not hitherto healthy implicit.

REFERENCES:

1. H. Manuel, “Pancreatic cancer,” The New England Journal of Medicine, vol. 362, no. 17, pp. 1605–1617, 2010.

2. H. A. Burris III, M. J. Moore, J. Andersen et al., “Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial,” Journal of Clinical Oncology, vol. 15, no. 6, pp. 2403–2413, 1997.

3. T. Conroy, F. Desseigne, M. Ychou et al., “FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer,”

4. Dreyer C., Krey G., Keller H., Givel F., Helftenbein G. and Wahli W. (1992): Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell, 68, 879–887.

5. Isseman I. and Green S. (1990): Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 347, 645–650.

6. Barger P. M. and Kelly D. P. (2000): PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc. Med., 10, 238–245.

7. G. Kristiansen, J. Jacob, A. C. Buckendahl et al., “Peroxisome proliferator-activated receptor γ is highly expressed in pancreatic cancer and is associated with shorter overall survival times,” Clinical Cancer Research, vol. 12, no. 21, pp. 6444– 6451, 2006.

8. Auboeuf D., Rieusset J., Fajas L., Vallier P., Frering V., Riou J. P., Staels B., Auwerx J., Laville M. and Vidal H. (1997): Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes, 46, 1319–1327.

9. Mukherjee R., Jow L., Croston G. E., Paternity J. R. (1997): Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR-gamma2 versus PPAR-gamma1 and activation with retinoid X receptor agonists and antagonists. J. Biol. Chem., 272, 8071–8076.

10. Dressel U., Allen T. L., Pippal J. B., Rohde P. R., Lau P. and Muscat G. E. (2003): The peroxisome proliferator--activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol. Endocrinol., 17, 2477–2493.

11. Leibowitz M. D., Fiévet C., Hennuyer N., Peinado--Onsurbe J., Duez H., Bergera J., Cullinan C. A., Sparrow C. P., Baffic J., Berger G. D., Santini C., Marquis R. W., Tolman R. L., Smith R. G., Moller D. E. and Auwerx J. (2000): Activation of PPARdelta alters lipid metabolism in db/db mice. FEBS Lett., 473, 333 336.

12. Tanaka T., Yamamoto J., Iwasaki S., Asaba H., Hamura H., Ikeda Y., Watanabe M., Magoori K., Ioka R. X., Tachibana K., Watanabe Y., Uchiyama Y., Sumi K., Iguchi H., Ito S., Doi T., Hamakubo T., Naito M., Auwerx J., Yanagisawa M., Kodama T. and Sakai J. (2003): Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl. Acad. Sci. USA,100, 15924–15929.

13. Wang Y. X., Zhang C. L., Yu R. T., Cho H. K., Nelson M. C., Bayuga-Ocampo C. R., Ham J., Kang H. and Evans R. M. (2004): Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol., 2, e294.

14. Kahn B. B. and Flier J. S. (2000): Obesity and insulin resistance. J. Clin. Invest., 106, 473–481.

15. Lemberger T., Desvergne B. and Wahli W. (1996): Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol., 12, 335–363.

16. Spiegelman B. M. (1998): PPAR-gamma: Adipogenic regulator and thiazolidinedione receptor. Diabetes, 47, 507–514.\

17. IJpenberg A., Jeannin E., Wahli W. and Desvergne B. (1997): Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. J. Biol. Chem., 272, 20108–20117.

18. Kliewer S. A., Umesono K., Mangelsdorf D. J. and Evans R. M. (1992): Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature, 355, 446–449.

19. Kliewer S. A., Umesono K., Noonan D. J., Heyman R. A. and Evans R. M. (1992): Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature, 358, 771–774.

20. Forman B. M., Chen J. and Evans R. M. (1997): Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA, 94, 4312–4317.

21. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M. and Evans R. M. (1995): 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-gamma. Cell, 83, 803–812.

22. Kliewer S. A., Sundseth S. S., Jones S. A., Brown P. J., Wisely G. B., Koble C. S., Devchand P., Wahli W., Willson T. M., Lenhard J. M. and Lehmann J. M. (1997): Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA, 94, 4318–4323.

23. Henke B. R., Blanchard S. G., Brackeen M. F., Brown K. K., Cobb J. E., Collins J. L., Harrington W. W. Jr., Hashim M. A., Hull-Ryde E. A., Kaldor I., Kliewer S. A., Lake D. H., Leesnitzer L. M., Lehmann J. M., Lenhard J. M., Orband-Miller L. A., Miller J. F., Mook R. A. Jr., Noble S. A., Oliver W. Jr., Parks D. J., Plunket K. D., Szewczyk J. R. and Willson T. M. (1998): N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem., 41, 5020–5036.

24. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M. and Kliewer S. A. (1995): An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR--gamma). J. Biol. Chem., 270, 12953–12956.

25. Kliewer S. A., Lenhard J. M., Willson T. M., Patel I., Morris D. C. and Lehmann J. M. (1995): A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell, 83, 813–819.

26. Nagy L., Tontonoz P., Alvarez J. G., Chen H. and Evans R. M. (1998): Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-gamma. Cell, 93, 229–240.

27. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M. and Kliewer S. A. (1995): An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR--gamma). J. Biol. Chem., 270, 12953–12956.

28. Rangwala S. M. and Lazar M. A. (2004): Peroxisome proliferator- activated receptor gamma in diabetes and metabolism. Trends Pharmacol. Sci., 25, 331–336.

29. H. Walczak, K. Iwai, and I. Dikic, “Generation and physiological roles of linear ubiquitin chains,” BMC Biology, vol. 10, article 23, 6 pages, 2012.

30. A. A. Chanan-Khan, I. Borrello, K. P. Lee, and D. E. Reece, “Development of target-specific treatments in multiple myeloma,” British Journal of Haematology, vol. 151, no. 1, pp. 3–15, 2010.

31. Owen G. I. and Zelent A. (2000): Origins and evolutionary diversification of nuclear receptor superfamily. CMLS Cell. Mol. Life Sci., 57, 809–827.

32. Werman A., Hollenberg A., Solanes G., Bjørbaek C., Vidal-Puig A. J. and Flier J. S. (1997): Ligand-independent activation domain in the N terminus of peroxisome proliferator- activated receptor gamma (PPARγ). J. Biol. Chem., 272, 20230–20235.

33. Auwerx J. (1999): PPAR-gamma, the ultimate thrifty gene. Diabetologia, 42, 1033–1049.

34. Shao D., Rangwala S. M., Bailey S. T., Krakow S. L., Reginato M. J. and Lazar M. A. (1998): Interdomain communication regulating ligand binding by PPAR-gamma. Nature, 396, 377–380.

35. Hu E., Kim J. B., Sarraf P. and Spiegelman B. M. (1996): Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science, 274, 2100–2103.

36. Nolte R. T., Wisely G. B., Westin S., Cobb J. E., Lambert M. H., Kurokawa R., Rosenfeld M. G., Willson T. M., Glass C. K. and Milburn M. V. (1998): Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature, 395, 137–143.

37. Berger J. and Moller D. E. (2002): The mechanisms of action of PPARs. Annu. Rev. Med., 53, 409–435.

38. Uppenberg J., Svensson C., Jaki M., Bertilsson G., Jendeberg L. and Berkenstam A. (1998): Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma. J. Biol. Chem., 273, 31108–31112.

39. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M. and Kliewer S. A. (1995): An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR--gamma). J. Biol. Chem., 270, 12953–12956.

40. Lu I. L., Huang C. F., Peng Y. H., Lin Y. T., Hsieh H. P., Chen C. T., Lien T. W., Lee H. J., Mahindroo N., Prakash E., Yueh A., Chen H. Y., Goparaju C. M., Chen X., Liao C. C., Chao Y. S., Hsu J. T. and Wu S. Y. (2006): Structure--based drug design of a novel family of PPARγ partial agonist: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities. J. Med. Chem., 49, 2703–2712.

41. Xu H. E., Lambert M. H., Montana V. G., Plunket K. D., Moore L. B., Collins J. L., Oplinger J. A., Kliewer S. A., Gampe R. T. Jr, McKee D. D., Moore J. T. and Willson T. M. (2001): Structural determinant of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA, 98, 13919–13924.

42. Forman B. M., Chen J. and Evans R. M. (1997): Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA, 94, 4312–4317.

43. Kliewer S. A., Sundseth S. S., Jones S. A., Brown P. J., Wisely G. B., Koble C. S., Devchand P., Wahli W., Willson T. M., Lenhard J. M. and Lehmann J. M. (1997): Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA, 94, 4318–4323.

44. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M. and Evans R. M. (1995): 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-gamma. Cell, 83, 803–812.

45. Kliewer S. A., Lenhard J. M., Willson T. M., Patel I., Morris D. C. and Lehmann J. M. (1995): A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell, 83, 813–819.

46. Nagy L., Tontonoz P., Alvarez J. G., Chen H. and Evans R. M. (1998): Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-gamma. Cell, 93, 229–240.

47. Brzozowski A. M., Pike A. C., Dauter Z., Hubbard R. E., Bonn T., Engstrom O., Ohman L., Greene G. L., Gustafsson J. A. and Carlquist M. (1997): Molecular basis of agonism and antagonism in the oestrogen receptor. Nature, 389, 753–758.

48. Renaud J. P., Rochel N., Ruff M., Vivat V., Chambon P., Gronemeyer H. and Moras D. (1995): Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature, 378, 681–689.

49. Tzameli I., Fang H., Ollero M., Shi H., Hamm J. K., Kievit P., Hollenberg A.N. and Flier J. S. (2004): Regulated production of a peroxisome proliferator-activated receptor--gamma ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes. J. Biol. Chem., 279, 36093–36102.

50. Lehmann J. M., Lenhard J. M., Oliver B. B., Ringold G. M. and Kliewer S. A. (1997): Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non steroidal anti-inflammatory drugs. J. Biol. Chem., 272, 3406–3410.

51. Tontonoz P., Hu E. and Speiegelman B. M. (1995): Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor--gamma. Curr. Opin. Genet. Dev., 5, 571–576

52. Kletzien R. F., Clarke S. D. and Ulrich R. G. (1992): Enhancement of adipocyte differentiation by an insulin--sensitizing agent. Mol. Pharmacol., 41, 393–398.

53. Willson T. M., Cobb J. E., Cowan D. J., Wiethe R. W., Correa I. D., Prakash S. R., Beck K. D., Moore L. B.,Kliewer S. A. and Lehmann J. M. (1996): The structure activity relationship between peroxisome proliferator--activated receptor-gamma agonism, and anti-hyperglycaemic activity of thiazolidinediones. J. Med. Chem., 39, 665–668.

54. Reifel-Miller A., Otto K., Hawkins E., Barr R., Bensch W. R., Bull C., Dana S., Klausing K., Martin J. A., Rafaeloff--Phail R., Rafizadeh-Montrose C., Rhodes G., Robey R., Rojo I., Rungta D., Snyder D., Wilbur K., Zhang T., ZinkR., Warshawsky A. and Brozinick J. T. (2005): A peroxisome proliferator-activated receptor alpha/gamma dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia. Mol. Endocrinol., 19, 1593–1605.

55. M. Toyota, Y. Miyazaki, S. Kitamura et al., “Peroxisome proliferator-activated receptor γ reduces the growth rate of ancreatic cancer cells through the reduction of cyclin D1,” Life Sciences, vol. 70, no. 13, pp. 1565–1575, 2002.

56. S. Kawa, T. Nikaido, H. Unno, N. Usuda, K. Nakayama, and K. Kiyosawa, “Growth inhibition and differentiation of pancreatic cancer cell lines by PPARγ ligand troglitazone,” Pancreas, vol. 24, no. 1, pp. 1–7, 2002.

57. K. Hashimoto, B. J. Farrow, and B. M. Evers, “Activation and role of MAP Kinases in 15d-PGJ2-induced apoptosis in the human pancreatic cancer cell line MIA PaCa-2,” Pancreas, vol. 28, no. 2, pp. 153–159, 2004.

58. W. Motomura, M. Nagamine, S. Tanno et al., “Inhibition of cell invasion and morphological change by troglitazone in human pancreatic cancer cells,” Journal of Gastroenterology, vol. 39, no. 5, pp. 461–468, 2004.

59. H. Sawai, J. Liu, H. A. Reber, O. J. Hines, and G. Eibl, “Activation of peroxisome proliferator-activated receptor-γ decreases pancreatic cancer cell invasion throughmodulation of the plasminogen activator system,” Molecular Cancer Research, vol. 4, no. 3, pp. 159–167, 2006.

60. A. Galli, E. Ceni, D. W. Crabb et al., “Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARγ independent mechanisms,” Gut, vol. 53, no. 11, pp. 1688–1697, 2004.

61. E. Ceni, T. Mello, M. Tarocchi et al., “Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells,” World Journal of Gastroenterology, vol. 11, no. 8, pp. 1122–1130, 2005.

62. M. Tsujie, S. Nakamori, J. Okami et al., “Thiazolidinediones inhibit growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferator-activated receptor γ/retinoid X receptor α pathway,” Experimental Cell Research, vol. 289, no. 1, pp. 143–151, 2003.

63. Y. Takeuchi, M. Takahashi, K. Sakano et al., “Suppression of N-nitrosobis(2-oxopropyl) amine-induced pancreatic carcinogenesis in hamsters by pioglitazone, a ligand of peroxisome proliferator-activated receptor γ,” Carcinogenesis, vol. 28, no. 8, pp. 1692–1696, 2007.

64. Y.W. Dong, X. P. Wang, and K. Wu, “Suppression of pancreatic carcinoma growth by activating peroxisome proliferatoractivated receptor γ involves angiogenesis inhibition,” World Journal of Gastroenterology, vol. 15, no. 4, pp. 441–448, 2009.

65. A. Nakajima, A. Tomimoto, K. Fujita et al., “Inhibition of peroxisome proliferator-activated receptor γ activity suppresses pancreatic cancer cell motility,” Cancer Science, vol. 99, no. 10, pp. 1892–1900, 2008.

66. Andrzej Zieleniak, Marzena Wojcik, and Lucyna A. Wozniok; 2008, Structure and Physiological Functions of The Human Peroxisome Proliferator – Activated receptor- γ; Arch. Immunol. Ther. Exp. 2008, 56,331-345.

67. Athina Stravodimou, Gianluigi Mazzoccoli, and Ioannis A. Voutsadalas; 2012, Review Article: Peroxisome Proliferator – Activated Receptor Gamma and Regulations by the Ubiquitin – Proteasom System in Pancreatic Cancer; doi: 10.1155/2012/ 367450.

68. Uysal K. T., Wiesbrock S. M., Marino M. W. and Hotamisligil G. S. (1997): Protection from obesity--induced insulin resistance in mice lacking TNF-alpha function. Nature, 389, 610–614.

69. Ventre J., Doebber T., Wu M., MacNaul K., Stevens K., Pasparakis M., Kollias G. and Moller D. E. (1997): Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes, 46, 1526–1531.

70. Miles P. D., Romeo O. M., Higo K., Cohen A., Rafaat K. and Olefsky J. M. (1997): TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes, 46, 1678–1683.

71. Shibasaki M., Takahashi K., Itou T., Bujo H. and Saito Y. (2003): A PPAR agonist improves TNF-alpha-induced insulin resistance of adipose tissue in mice. Biochem. Biophys. Res. Commun., 309, 419–424.

72. De Vos P., Lefebvre A. M., Miller S. G., Guerre-Millo M., Wong K., Saladin R., Hamann L. G., Staels B., Briggs M. R. and Auwerx J. (1996): Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J. Clin. Invest., 98, 1004–1009.

73. Kallen C. B. and Lazar M. A. (1996): Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc. Natl. Acad. Sci. USA, 93, 5793–5796.

74. Müller G., Ertl J., Gerl M. and Preibisch G. (1997): Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J. Biol. Chem., 272, 10585–10593.

75. Shimomura I., Hammer R. E., Ikemoto S., Brown M. S. and Goldstein J. L. (1999): Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature, 401, 73–76.

76. Yaspelkis B. B., Ansari L., Ramey E. L., Holland G. J. and Loy S. F. (1999): Chronic leptin administration increases insulin-stimulated skeletal muscle glucose uptake and transport. Metabolism, 48, 671–676.

77. Moon B., Kwan J. J., Duddy N., Sweeney G. and Begum N. (2003): Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. Am. J. Physiol. Endocrinol. Metab., 285, E106–115.

78. Steppan C. M., Bailey S. T., Bhat S., Brown E. J., Banerjee R. R., Wright C. M., Patel H. R., Ahima R. S. and Lazar M. A. (2001): The hormone resistin links obesity to diabetes. Nature, 409, 307–312.

79. Steppan C. M. and Lazar M. A. (2002): Resistin and obesity- associated insulin resistance. Trends Endocrinol. Metab., 13, 18–23.

80. Le Lay S., Boucher J., Rey A., Castan-Laurell I., Krief S., Ferré P., Valet P. and Dugail I. (2001): Decreased resistin expression in mice with different sensitivities to a high-fat diet. Biochem. Biophys. Res. Commun., 289, 564–567.

81. Milan G., Granzotto M., Scarda A., Calcagno A., Pagano C., Federspil G. and Vettor R. (2002): Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes. Res., 10, 1095–1103.

82. Stephens J. M. and Pekala P. H. (1992): Transcriptional repression of the C/EBP-alpha and GLUT4 genes in 3T3--L1 adipocytes by tumor necrosis factor-alpha. Regulation is coordinate and independent of protein synthesis. J. Biol. Chem., 267, 13580–13584.

83. Shojima N., Sakoda H., Ogihara T., Fujishiro M., Katagiri H., Anai M., Onishi Y., Ono H., Inukai K., Abe M., Fukushima Y., Kikuchi M., Oka Y. and Asano T. (2002): Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes, 51, 1737–1744.

84. Hartman H. B., Hu X., Tyler K. X., Dalal C. K. and Lazar M. A. (2002): Mechanisms regulating adipocyte expression of resistin. J. Biol. Chem., 277, 19754–19761.

85. Fukui Y. and Motojima K. (2002): Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator-activated receptor alpha. Diabetes Obes. Metab., 4, 342–345.

86. Way J. M., Görgün C. Z., Tong Q., Uysal K. T., Brown K. K., Harrington W. W., Oliver W. R. Jr., Willson T. M., Kliewer S. A. and Hotamisligil G. S. (2001): Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J. Biol. Chem., 276, 25651– 25653.

87. Fasshauer M., Klein J., Neumann S., Eszlinger M. and Paschke R. (2001): Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun., 288, 1027–1031.

88. Fehmann H. C. and Heyn J. (2002): Plasma resistin levels in patients with type 1 and type 2 diabetes mellitus and in healthy controls. Horm. Metab. Res., 34, 671–673.

89. Lee J. H., Chan J. L., Yiannakouris N., Kontogianni M., Estrada E., Seip R., Orlova C. and Mantzoros C. S. (2003): Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J. Clin. Endocrinol. Metab., 88, 4848–4856.

90. Jackson M. B., Osei S. Y. and Ahima R. S. (2005): The endocrine role of adipose tissue: focus on adiponectin and resistin. Curr. Opin. Endocrinol. Diab., 12, 163.

91. Hu E., Liang P. and Spiegelman B. M. (1996): AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem., 271, 10697–10703.

92. Arita Y., Kihara S., Ouchi N., Takahashi M., Maeda K., Miyagawa J., Hotta K., Shimomura I., Nakamura T., Miyaoka K., Kuriyama H., Nishida M., Yamashita S., Okubo K., Matsubara K., Muraguchi M., Ohmoto Y., Funahashi T. and Matsuzawa Y. (1999): Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun., 257, 79–83.

93. Weyer C., Funahashi T., Tanaka S., Hotta K., Matsuzawa Y., Pratley R. E. and Tataranni P. A. (2001): Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J. Clin. Endocrinol. Metab., 86, 1930–1935.

94. Combs T. P., Wagner J.A., Berger J., Doebber T., Wang W. J., Zhang B. B., Tanen M., Berg A. H., O’Rahilly S., Savage D. B., Chatterjee K., Weiss S., Larson P. J., Gottesdiener K. M., Gertz B. J., Charron M. J., Scherer P. E. and Moller D. E. (2002): Induction of adipocyte complement- related protein of 30 kilodaltons by PPAR-γ agonists: a potential mechanism of insulin sensitization. Endocrinology, 143, 998 –1007.

95. Hirose H., Kawai T., Yamamoto Y., Taniyama M., Tomita M., Matsubara K., Okazaki Y., Ishii T., Oguma Y., Takei I. and Saruta T. (2002): Effects of pioglitazone on metabolic parameters, body fat distribution and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism, 51, 314 –317.

96. Maeda N., Takahashi M., Funahashi T., Kihara S., Nishizawa H., Kishida K., Nagaretani H., Matsuda M., Komuro R., Ouchi N., Kuriyama H., Hotta K., Nakamura T., Shimomura I. and Matsuzawa Y. (2001): PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes, 50, 2094–2099.

97. Yang W. S., Jeng C. Y., Wu T. J., Tanaka S., Funahashi T., Matsuzawa Y., Wang J. P., Chen C. L., Tai T. Y. and Chuang L. M. (2002): Synthetic peroxisome proliferator--activated receptor-γ agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care, 25, 376–380.

98. Yu J. G., Javorschi S., Hevener A. L., Kruszynska Y. T., Norman R. A., Sinha M. and Olefsky J. M. (2002): The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes, 51, 2968–2974.

99. Yamauchi T., Kamon J., Waki H., Terauchi Y., Kubota N., Hara K., Mori Y., Ide T., Murakami K., Tsuboyama--Kasaoka N., Ezaki O., Akanuma Y., Gavrilova O., Vinson C., Reitman M. L., Kagechika H., Shudo K., Yoda M., Nakano Y., Tobe K., Nagai R., Kimura S., Tomita M., Froguel P. and Kadowaki T. (2001): The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med., 7, 941–946.

100. Combs T. P., Berg A. H., Obici S., Scherer P. E. and Rossetti L. (2001): Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J. Clin. Invest., 108, 1875–1881.

101. Mohamed-Ali V., Goodrick S., Rawesh A., Katz D. R., Miles J. M., Yudkin J.S., Klein S. and Coppack S. W. (1997): Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab., 82, 4196–4200.

102. Bastard J. P., Jardel C., Bruckert E., Blondy P., Capeau J., Laville M., Vidal H. and Hainque B. (2000): Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J. Clin. Endocrinol. Metab., 85, 3338–3342.

103. Hotamisligil G. S. and Spiegelman B. M. (1994): Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes, 43, 1271–1278.

104. Lang C. H., Dobrescu C. and Bagby G. J. (1992): Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology, 130, 43–52.

105. Hotamisligil G. S., Shargill N. S. and Spiegelman B. M. (1993): Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science, 259, 87–91.

Received on 29.05.2020 Modified on 19.06.2020

Asian J. Res. Pharm. Sci. 2020; 10(3):224-232.

DOI: 10.5958/2231-5659.2020.00041.7