The metabolic syndrome has become one of the major public health challenges worldwide (1,2) and is thought to result from obesity and obesity-linked insulin resistance, the combination of which promotes diabetes, hypertension, hyperlipidemia, and cardiovascular diseases (1,2). Obesity, defined as increased adipose tissue mass, is mainly characterized by adipocyte hypertrophy, especially in adulthood (1,2). Adipose tissue serves as the site of triglyceride storage and free fatty acid (FFA)/glycerol release in response to changing energy demands (1). Adipose tissue also participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active “adipokines,” such as FFA (3), tumor necrosis factor (TNF)-α (4), resistin (5), and leptin (6). Although the association of obesity and insulin resistance has been recognized, the mechanisms by which obesity causes systemic insulin resistance largely remain unclear. One such mechanism is upregulation of insulin resistance–inducing adipokines, such as FFA, TNF-α, and resistin (Fig. 1). In contrast to such insulin resistance–causing adipokines, adiponectin, as well as leptin, is one of the adipokines that directly sensitizes the body to insulin, and its expression and serum levels are known to be upregulated by thiazolidinediones (TZDs), a group of insulin sensitizers. In this review, we describe recent progress in research into the role of adiponectin in amelioration of insulin resistance and diabetes by TZDs.

TZDs have been shown to increase insulin action in skeletal muscle and liver in animal models of obesity-linked insulin resistance and diabetes, and TZDs have been widely used for the treatment of type 2 diabetes (710). Peroxisome proliferator–activated receptor-γ is a family of ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and plays a critical role in the regulation of adipocyte differentiation (1115). TZDs bind to and activate peroxisome proliferator–activated receptor-γ in adipose tissue, thereby promoting adipose tissue differentiation and increasing the number of small adipocytes that are more sensitive to insulin and decreasing the number of large adipocytes by inducing apoptosis (1619). Because peroxisome proliferator–activated receptor-γ is predominantly expressed in adipose tissue, it is reasonable to speculate that the effect of TZDs on insulin resistance in skeletal muscle and the liver is mediated largely via the effects of TZDs on adipose tissue, including alterations of adipokine expression and secretion by adipocytes (10,1721). Generation of small insulin-sensitive adipocytes by TZDs lowers circulating serum FFA levels and downregulates the production and secretion of TNF-α and resistin (4,5,16,2023), subsequently ameliorating insulin resistance (20,21) (Fig. 1). However, it remains to be elucidated how these effects by TZDs participate in the amelioration of insulin resistance in skeletal muscle and the liver.

Adiponectin is an adipose tissue–derived secreted protein that circulates in serum (2427). We previously reported that replenishment of adiponectin ameliorated insulin resistance in obese mice with decreased serum adiponectin levels and that a combination of physiological doses of adiponectin and leptin reversed insulin resistance in lipoatrophic mice (28). Independently, administration of adiponectin has been reported to decrease plasma glucose levels by suppressing hepatic glucose production (29,30), and administration of globular adiponectin reportedly lowers elevated fatty acid concentrations by oxidizing fatty acids in muscle (31). In fact, adiponectin deficient (adipo−/−) mice are insulin resistant and glucose intolerant (3234). Previous studies have shown that adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver by activating AMP-activated protein kinase (AMPK) (35) through its specific receptors, AdipoR1 and AdipoR2 (36). As a result, adiponectin has come to be recognized as a major insulin-sensitizing hormone. The expression and serum levels of adiponectin have been shown to be upregulated by TZDs (28,3739). The expression of adiponectin was increased during adipocyte differentiation in 3T3L1 adipocytes and also increased with rosiglitazone in differentiated 3T3L1 adipocytes (28) (Fig. 2). Moreover, serum adiponectin levels in obese diabetic mice and patients with type 2 diabetes were increased after pioglitazone administration (Fig. 2) (28,37,38). These findings suggest that TZDs may upregulate adiponectin via generating small adipocytes that abundantly express and secrete adiponectin and/or directly activating adiponectin gene transcription (39).

Adiponectin is known to form three major characteristic multimers in serum: a trimer (low-molecular-weight), a hexamer (middle-molecular-weight), and 12–18mer (high-molecular-weight [HMW]) adiponectin (40). Several observations suggest that HMW adiponectin is the more active form of the protein and appears to have a more relevant role in improving insulin sensitivity and exerting an anti-diabetes effect (4143). Moreover, changes in the ratio of serum HMW adiponectin to total adiponectin correlate with improvement in insulin sensitivity in both mice and diabetic patients, whereas changes in total serum adiponectin levels do not show good correlations at the individual level (42). We investigated whether TZDs affect the forms of serum adiponectin in obese diabetic mice models and found that both HMW adiponectin and the ratio of HMW to total adiponectin were decreased in vehicle-treated obese and diabetic KKAy mice compared with wild-type KK mice (Fig. 3) (44). While the restriction of food intake by pair-fed mice partially restored the decrease in both HMW adiponectin and the ratio of HMW to total adiponectin in KKAy mice (Fig. 3) (44), rosiglitazone treatment dramatically increased total adiponectin and the ratio of HMW to total adiponectin (Fig. 3) (44). It is noteworthy that the ratio of serum HMW adiponectin to total adiponectin correlated more significantly with glucose tolerance or insulin levels than the total adiponectin level (43), suggesting that serum HMW adiponectin alterations may be more relevant to the prediction of insulin resistance than serum total adiponectin alterations. Consistent with this, total adiponectin, HMW adiponectin, low-molecular-weight adiponectin, and the HMW-to-total adiponectin ratio all correlated significantly with key features of central obesity and the insulin-stimulated glucose disposal rate (45). However, HMW levels, not total adiponectin levels, are primarily responsible for these relationships, suggesting that measurement of the HMW levels may be superior to measuring total adiponectin (45).

Since adiponectin is an insulin-sensitizing adipokine, it is reasonable to speculate that TZDs increase insulin sensitivity, at least in part, by increasing serum adiponectin. However, whether the TZD-induced increase in serum adiponectin is causally involved in TZD-mediated insulin-sensitizing effects has not been addressed experimentally. To address this issue, adipo−/−ob/ob mice with a C57Bl/6 background were used to investigate whether the TZD pioglitazone is capable of ameliorating insulin resistance in the absence of adiponectin (37). The absence of adiponectin had no effect on either the obesity or the diabetic phenotype of ob/ob and adipo−/−ob/ob mice. Ob/ob mice exhibited diabetic glucose tolerance, and the diabetes was significantly improved in association with significant upregulation of serum adiponectin levels with low-dose pioglitazone treatment (Fig. 4A). Adipo−/−ob/ob mice showed comparable diabetic glucose tolerance to ob/ob mice, but the diabetes was not improved by low-dose pioglitazone treatment (Fig. 4B). Hyperinsulinemic-euglycemic clamp studies to measure insulin sensitivity in the liver and skeletal muscle revealed that glucose infusion rates (GIRs) were comparable in ob/ob and adipo−/−ob/ob mice (Fig. 4C). A low dose of pioglitazone increased the GIR of ob/ob mice but not of adipo−/−ob/ob mice (Fig. 4C). The amelioration of insulin resistance in ob/ob mice was, at least in part, due to decreased endogenous glucose production (EGP) (Fig. 4D). Rate of glucose disappearance (Rd) values were indistinguishable in all mice groups (Fig. 4E). Because EGP was decreased, hepatic PEPCK expression and AMPK activity were examined. Low doses of pioglitazone significantly decreased PEPCK expression in ob/ob, but not adipo−/−ob/ob, mice (Fig. 4F). In addition, AMPK phosphorylation in ob/ob mice was significantly increased by low doses of pioglitazone, but was unchanged in adipo−/−ob/ob mice (Fig. 4G). These findings indicate that low doses of pioglitazone ameliorate diabetes and hepatic, but not muscle, insulin resistance in mice with an ob/ob background in an adiponectin-dependent manner via, at least in part, decreased gluconeogenesis and increased AMPK activation.

Increased adiponectin levels induced by high doses of pioglitazone were indistinguishable from those by low doses of pioglitazone in the ob/ob mice (Fig. 4A, inset; Fig. 5A, inset). The diabetes of ob/ob mice was again significantly ameliorated by high doses of pioglitazone (Fig. 5A). Interestingly, adipo−/−ob/ob mice also displayed significant amelioration of diabetes, being similar to the levels seen in ob/ob mice (Fig. 5B). Hyperinsulinemic-euglycemic clamp studies showed that the GIR of ob/ob mice again significantly increased after high doses of pioglitazone (Fig. 5C). Interestingly, the GIR of adipo−/−ob/ob mice also increased, indicating that insulin resistance in adipo−/−ob/ob mice had improved (Fig. 5C). The EGP decreased only in ob/ob mice as seen after low doses of pioglitazone treatment (Fig. 5D), but the Rd increased in ob/ob and adipo−/−ob/ob mice to a similar degree after high doses of pioglitazone (Fig. 5E). High doses of pioglitazone decreased PEPCK expression (Fig. 5F) and increased AMPK phosphorylation (Fig. 5G) in ob/ob mice, but not in adipo−/−ob/ob mice. These findings suggest that the amelioration of diabetes and insulin resistance in adipo−/−ob/ob mice was, at least in part, due to increased glucose uptake in skeletal muscle.

As described above, TZDs increased the number of small adipocytes and decreased the number of large adipocytes, thereby ameliorating insulin resistance (16). To determine whether the presence of adiponectin is required for the occurrence of TZD-induced reduction of average adipocyte size, measurement of the adipocyte sizes in epididymal fat pads was performed. The adipocyte sizes of ob/ob and adipo−/−ob/ob mice were indistinguishable and remained unchanged after low doses of pioglitazone (Fig. 6A). High doses of pioglitazone, however, significantly reduced the adipocyte sizes of ob/ob and adipo−/−ob/ob mice to a similar degree (Fig. 6B). These results suggest that pioglitazone can induce a reduction in adipocyte size in the absence of adiponectin or leptin, or the absence of both. In addition, the serum FFA levels in ob/ob and adipo−/−ob/ob mice were unchanged after low-dose pioglitazone treatment (Fig. 6C), but were significantly reduced to a similar degree after high-dose pioglitazone treatment (Fig. 6D). Moreover, the expressions of TNF-α and resistin in adipose tissues of ob/ob and adipo−/−ob/ob mice were unchanged after low-dose pioglitazone (Fig. 6E and G), but were decreased after high-dose pioglitazone (Fig. 6F and H).

Although both high and low doses of pioglitazone ameliorated insulin resistance and diabetes, the underlying mechanisms may be distinct, albeit overlapped (37). We propose that there are two distinct pathways in the amelioration of insulin resistance induced by TZDs such as pioglitazone. One involves an adiponectin-dependent pathway and the other an adiponectin-independent pathway (Fig. 7) (46). Low doses of TZDs increase adiponectin concentrations at the transcriptional levels (39) without promoting adipocyte differentiation (16), causing amelioration of insulin resistance, increasing AMPK activation, and decreasing gluconeogenesis in the liver. On the other hand, independent of adiponectin, high doses of TZDs decrease adipocyte size, associated with decreased serum FFA levels and TNF-α and resistin expression, causing amelioration of insulin resistance in skeletal muscle (37). It seems likely that the increased adiponectin levels by TZDs also contribute to amelioration of skeletal muscle insulin resistance, and the decreased FFAs, TNF-α, and resistin by TZDs also contribute to amelioration of liver insulin resistance.

Scherer’s group reported that rosiglitazone also improved glucose tolerance in ob/ob mice, but only partial improvement was achieved in adipo−/−ob/ob mice (34). Moreover, rosiglitazone significantly increased AMPK activity in the livers of wild-type mice, whereas it had no effect on adipo−/− mice. In skeletal muscle, AMPK activity also significantly increased in wild-type mice, whereas no increase was detectable in adipo−/− mice. These data are in complete agreement with our data, suggesting that rosiglitazone also ameliorated glucose intolerance both via adiponectin-dependent and -independent pathways.

FIG. 1.

TZDs decrease insulin resistance–causing adipokines via generation of small adipocytes. TZDs promote adipocyte differentiation and increase the number of small adipocytes and decrease the number of large adipocytes. Generation of small insulin-sensitive adipocytes by TZDs lowers circulating serum FFA levels and downregulates the production and secretion of TNF-α and resistin, subsequently ameliorating insulin resistance.

FIG. 1.

TZDs decrease insulin resistance–causing adipokines via generation of small adipocytes. TZDs promote adipocyte differentiation and increase the number of small adipocytes and decrease the number of large adipocytes. Generation of small insulin-sensitive adipocytes by TZDs lowers circulating serum FFA levels and downregulates the production and secretion of TNF-α and resistin, subsequently ameliorating insulin resistance.

FIG. 2.

TZDs increase a major insulin-sensitizing adipokine, adiponectin (28,37,38). The expression of adiponectin was increased during adipocyte differentiation in 3T3L1 adipocytes and also increased with rosiglitazone in differentiated 3T3L1 adipocytes. Moreover, serum adiponectin levels in obese diabetic mice and patients with type 2 diabetes were increased after pioglitazone administration.

FIG. 2.

TZDs increase a major insulin-sensitizing adipokine, adiponectin (28,37,38). The expression of adiponectin was increased during adipocyte differentiation in 3T3L1 adipocytes and also increased with rosiglitazone in differentiated 3T3L1 adipocytes. Moreover, serum adiponectin levels in obese diabetic mice and patients with type 2 diabetes were increased after pioglitazone administration.

FIG. 3.

TZDs increased HMW adiponectin (44). Both HMW adiponectin and the ratio of HMW to total adiponectin decreased in obese diabetic KKAy mice compared with control KK mice. While the restriction of food intake partially restored the decrease in both HMW adiponectin and the ratio of HMW to total adiponectin in KKAy mice, rosiglitazone treatment dramatically increased total adiponectin and the ratio of HMW to total adiponectin. LMH, low-molecular-weight; MMW, medium-molecular-weight.

FIG. 3.

TZDs increased HMW adiponectin (44). Both HMW adiponectin and the ratio of HMW to total adiponectin decreased in obese diabetic KKAy mice compared with control KK mice. While the restriction of food intake partially restored the decrease in both HMW adiponectin and the ratio of HMW to total adiponectin in KKAy mice, rosiglitazone treatment dramatically increased total adiponectin and the ratio of HMW to total adiponectin. LMH, low-molecular-weight; MMW, medium-molecular-weight.

FIG. 4.

Low-dose pioglitazone treatment. Low doses of pioglitazone improve diabetes and insulin resistance in ob/ob mice, but not in adipo−/−ob/ob mice (37). A and B: Blood glucose levels during the oral glucose tolerance test of ob/ob (A) and adipo−/−ob/ob (B) mice. Insets of A and B indicate serum adiponectin levels of ob/ob (A, inset) and adipo−/−ob/ob (B, inset) mice not treated or treated with a low dose of pioglitazone (C-E). GIRs (C), EGP (D), and Rd values (E) of ob/ob and adipo−/−ob/ob mice in the clamp study are shown. F: PEPCK expression levels in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies. G: Phosphorylation of AMPK in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies.

FIG. 4.

Low-dose pioglitazone treatment. Low doses of pioglitazone improve diabetes and insulin resistance in ob/ob mice, but not in adipo−/−ob/ob mice (37). A and B: Blood glucose levels during the oral glucose tolerance test of ob/ob (A) and adipo−/−ob/ob (B) mice. Insets of A and B indicate serum adiponectin levels of ob/ob (A, inset) and adipo−/−ob/ob (B, inset) mice not treated or treated with a low dose of pioglitazone (C-E). GIRs (C), EGP (D), and Rd values (E) of ob/ob and adipo−/−ob/ob mice in the clamp study are shown. F: PEPCK expression levels in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies. G: Phosphorylation of AMPK in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies.

FIG. 5.

High-dose pioglitazone treatment. High doses of pioglitazone improve diabetes and insulin resistance in ob/ob and adipo−/−ob/ob mice (37). A and B: Blood glucose levels during an oral glucose tolerance test of ob/ob (A) and adipo−/−ob/ob (B) mice. Insets of A and B indicate serum adiponectin levels of ob/ob (A, inset) and adipo−/−ob/ob (B, inset) mice not treated or treated with high doses of pioglitazone. GIRs (C), EGP (D), and Rd values (E) of ob/ob and adipo−/−ob/ob mice in the clamp study are shown. F: PEPCK expression levels in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies. G: Phosphorylation of AMPK in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies.

FIG. 5.

High-dose pioglitazone treatment. High doses of pioglitazone improve diabetes and insulin resistance in ob/ob and adipo−/−ob/ob mice (37). A and B: Blood glucose levels during an oral glucose tolerance test of ob/ob (A) and adipo−/−ob/ob (B) mice. Insets of A and B indicate serum adiponectin levels of ob/ob (A, inset) and adipo−/−ob/ob (B, inset) mice not treated or treated with high doses of pioglitazone. GIRs (C), EGP (D), and Rd values (E) of ob/ob and adipo−/−ob/ob mice in the clamp study are shown. F: PEPCK expression levels in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies. G: Phosphorylation of AMPK in the livers of ob/ob and adipo−/−ob/ob mice after the clamp studies.

FIG. 6.

High-dose but not low-dose pioglitazone decreased adipocyte size, serum FFA levels, and expression levels of TNF-α and resistin in ob/ob and adipo−/−ob/ob mice (37). The adipocyte sizes (A and B) as well as serum FFA levels (C and D) in ob/ob and adipo−/−ob/ob mice were unchanged after low-dose pioglitazone treatment (A and C), but were significantly reduced to a similar degree after high-dose pioglitazone treatment (B and D). Moreover, the expressions of TNF-α (E and F) and resistin (G and H) in white adipose tissues of ob/ob and adipo−/−ob/ob mice were unchanged after low-dose pioglitazone (E and G), but decreased after high-dose pioglitazone (F and H).

FIG. 6.

High-dose but not low-dose pioglitazone decreased adipocyte size, serum FFA levels, and expression levels of TNF-α and resistin in ob/ob and adipo−/−ob/ob mice (37). The adipocyte sizes (A and B) as well as serum FFA levels (C and D) in ob/ob and adipo−/−ob/ob mice were unchanged after low-dose pioglitazone treatment (A and C), but were significantly reduced to a similar degree after high-dose pioglitazone treatment (B and D). Moreover, the expressions of TNF-α (E and F) and resistin (G and H) in white adipose tissues of ob/ob and adipo−/−ob/ob mice were unchanged after low-dose pioglitazone (E and G), but decreased after high-dose pioglitazone (F and H).

FIG. 7.

Adiponectin-dependent and -independent pathways in insulin-sensitizing and antidiabetic actions of TZDs (hypothesis). We hypothesize two distinct pathways in the amelioration of insulin resistance induced by TZDs, namely the adiponectin-dependent pathway and adiponectin-independent pathway. Low doses of TZDs increase adiponectin levels, without promoting adipocyte differentiation, causing amelioration of insulin resistance, increasing AMPK activation, and decreasing gluconeogenesis in the liver. On the other hand, despite the absence of adiponectin, high doses of TZDs decrease adipocyte size, serum FFA levels, and TNF-α and resistin expression, causing amelioration of insulin resistance in skeletal muscle.

FIG. 7.

Adiponectin-dependent and -independent pathways in insulin-sensitizing and antidiabetic actions of TZDs (hypothesis). We hypothesize two distinct pathways in the amelioration of insulin resistance induced by TZDs, namely the adiponectin-dependent pathway and adiponectin-independent pathway. Low doses of TZDs increase adiponectin levels, without promoting adipocyte differentiation, causing amelioration of insulin resistance, increasing AMPK activation, and decreasing gluconeogenesis in the liver. On the other hand, despite the absence of adiponectin, high doses of TZDs decrease adipocyte size, serum FFA levels, and TNF-α and resistin expression, causing amelioration of insulin resistance in skeletal muscle.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan; a grant from the Human Science Foundation (to T.K.); a Grant-in-Aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T.K.); a Grant-in-Aid for Creative Scientific Research (10NP0201) from the Japan Society for the Promotion of Science (to T.K.); and by Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health, Labor and Welfare of Japan (to T.K.).

1.
Spiegelman BM, Flier JS: Adipogenesis and obesity: rounding out the big picture.
Cell
87
:
377
–389,
1996
2.
Reaven GM: The fourth Musketeer: from Alexandre Dumas to Claude Bernard.
Diabetologia
38
:
3
–13,
1995
3.
Shulman GI: Cellular mechanisms of insulin resistance.
J Clin Invest
106
:
171
–176,
2000
4.
Hotamisligil GS: The role of TNFalpha and TNF receptors in obesity and insulin resistance.
J Intern Med
245
:
621
–625,
1999
5.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes.
Nature
409
:
307
–312,
2001
6.
Friedman JM: Obesity in the new millennium.
Nature
404
:
632
–634,
2000
7.
Bowen L, Stein PP, Stevenson R, Shulman GI: The effect of CP 68,722, a thiazolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats.
Metabolism
40
:
1025
–1030,
1991
8.
Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone.
N Engl J Med
331
:
1188
–1193,
1994
9.
Saltiel AR: New perspectives into the molecular pathogenesis and treatment of type 2 diabetes.
Cell
104
:
517
–529,
2001
10.
Yki-Jarvinen H: Thiazolidinediones.
N Engl J Med
351
:
1106
–1118,
2004
11.
Spiegelman BM: PPARγ adipogenic regulator and thiazolidinedione receptor.
Diabetes
47
:
507
–514,
1998
12.
Tontonoz P, Hu E, Spiegelman BM: Stimulation of adipogenesis in fibroblasts by PPARγ 2, a lipid-activated transcription factor.
Cell
79
:
1147
–1156,
1994
13.
Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM: PPARg is required for placental, cardiac, and adipose tissue development.
Mol Cell
4
:
585
–595,
1999
14.
Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Nagai R, Tobe K, Kimura S, Kadowaki T: PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.
Mol Cell
4
:
597
–609,
1999
15.
Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM: PPARγ is required for the differentiation of adipose tissue in vivo and in vitro.
Mol Cell
4
:
611
–617,
1999
16.
Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T: Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats.
J Clin Invest
101
:
1354
–1361,
1998
17.
Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity.
Nat Med
10
:
355
–361,
2004
18.
Rangwala SM, Lazar MA: Peroxisome proliferator-activated receptor gamma in diabetes and metabolism.
Trends Pharmacol Sci
25
:
331
–336,
2004
19.
Olefsky JM, Saltiel AR: PPAR gamma and the treatment of insulin resistance.
Trends Endocrinol Metab
11
:
362
–368,
2000
20.
Arner P: The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.
Trends Endocrinol Metab
14
:
137
–145,
2003
21.
Moller DE: New drug targets for type 2 diabetes and the metabolic syndrome.
Nature
414
:
821
–827,
2001
22.
Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T, Kubota N, Terauchi Y, Tobe K, Miki H, Tsuchida A, Akanuma Y, Nagai R, Kimura S, Kadowaki T: The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance.
J Biol Chem
276
:
41245
–41254,
2001
23.
Kershaw EE, Flier JS: Adipose tissue as an endocrine organ.
J Clin Endocrinol Metab
89
:
2548
–2556,
2004
24.
Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF: A novel serum protein similar to C1q, produced exclusively in adipocytes.
J Biol Chem
270
:
26746
–26749,
1995
25.
Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K: cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).
Biochem Biophys Res Commun
221
:
286
–296,
1996
26.
Hu E, Liang P, Spiegelman BM: AdipoQ is a novel adipose-specific gene dysregulated in obesity.
J Biol Chem
271
:
10697
–10703,
1996
27.
Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M: Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma.
J Biochem (Tokyo)
120
:
803
–812,
1996
28.
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 ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.
Nat Med
7
:
941
–946,
2001
29.
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
Nat Med
7
:
947
–953,
2001
30.
Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L: Endogenous glucose production is inhibited by the adipose-derived protein Acrp30.
J Clin Invest
108
:
1875
–1881,
2001
31.
Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF: Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.
Proc Natl Acad Sci U S A
98
:
2005
–2010,
2001
32.
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T: Disruption of adiponectin causes insulin resistance and neointimal formation.
J Biol Chem
277
:
25863
–25866,
2002
33.
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y: Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.
Nat Med
8
:
731
–737,
2002
34.
Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE: Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists.
J Biol Chem
281
:
2654
–2660,
2006
35.
Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.
Nat Med
8
:
1288
–1295,
2002
36.
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T: Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.
Nature
423
:
762
–769,
2003
37.
Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T: Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways.
J Biol Chem
281
:
8748
–8755,
2006
38.
Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T: 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,
2002
39.
Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I: Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.
Diabetes
52
:
1655
–1663,
2003
40.
Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE: Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity.
J Biol Chem
278
:
9073
–9085,
2003
41.
Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, Kimura S, Nagai R, Kadowaki T: Impaired multimerization of human adiponectin mutants associated with diabetes: Molecular structure and multimer formation of adiponectin.
J Biol Chem
278
:
40352
–40363,
2003
42.
Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT: Adiponectin multimeric complexes and the metabolic syndrome trait cluster.
Diabetes
55
:
249
–259,
2006
43.
Fisher FF, Trujillo ME, Hanif W, Barnett AH, McTernan PG, Scherer PE, Kumar S: Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males.
Diabetologia
48
:
1084
–1087,
2005
44.
Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T, Kadowaki T: Peroxisome proliferator-activated receptor (PPAR) alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination.
Diabetes
54
:
3358
–3370,
2005
45.
Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE: Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.
J Biol Chem
279
:
12152
–12162,
2004
46.
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ucki K, Tobe K: Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
J Clin Invest
116
:
1784
–1792,
2006