Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect

Adiponectin (Adipoq), a peptide hormone secreted from the white adipose tissue, may play a role in the anti-aging and/or anti-tumor effects of calorie restriction (CR). We analyzed metabolic traits in Adipoq gene-overexpressing mice fed ad libitum with a regular diet (RD) or a high-fat diet (HFD), or fed 30% CR of RD initiated at 12. weeks of age. Adipoq-RD and -HFD mice at 6. months of age showed reduced blood glucose and insulin concentrations, and thus increased insulin sensitivity, compared with WT mice fed a RD or a HFD. In the epididymal white adipose tissue in Adipoq mice, senescence-like changes such as upregulation of p53 protein and of biomarkers of inflammation, Cd68 and Ccl2 mRNA, were ameliorated compared with WT-RD and WT-HFD mouse tissues. Resistance to stress induced by lipopolysaccharide was also strengthened in Adipoq mice compared with WT mice. These metabolic changes and stress resistance were also noted in the WT-CR mice, suggesting that Adipoq plays a part in the effect of CR. In contrast, in an allograft tumor growth model, tumor growth was not inhibited in Adipoq mice. The present findings suggest that Adipoq plays a part in the anti-aging, but not in the anti-tumor, effects of CR

Hyperadiponectinemia enhances bone formation in mice

<p>Abstract</p> <p>Background</p> <p>There is growing evidence that adiponectin, a physiologically active polypeptide secreted by adipocytes, controls not only adipose tissue but also bone metabolism. However, a role for adiponectin in bone development remains controversial.</p> <p>Methods</p> <p>We therefore investigated the endocrine effects of adiponectin on bone metabolism using 12-week-old male transgenic (Ad-Tg) mice with significant hyperadiponectinemia overexpressing human full-length adiponectin in the liver.</p> <p>Results</p> <p>In Ad-Tg mice, the serum level of osteocalcin was significantly increased, but the levels of RANKL, osteoprotegerin, and TRAP5b were not. Bone mass was significantly greater in Ad-Tg mice with increased bone formation. In contrast, bone resorption parameters including the number of osteoclasts and eroded surface area did not differ between Ad-Tg and their littermates.</p> <p>Conclusions</p> <p>These findings demonstrate that hyperadiponectinemia enhances bone formation in mice.</p

Selective modulation of Wnt ligands and their receptors in adipose tissue by chronic hyperadiponectinemia.

BACKGROUND: Adiponectin-transgenic mice had many small adipocytes in both subcutaneous and visceral adipose tissues, and showed higher sensitivity to insulin, longer life span, and reduced chronic inflammation. We hypothesized that adiponectin regulates Wnt signaling in adipocytes and thereby modulates adipocyte proliferation and chronic inflammation in adipose tissue. MATERIALS AND METHODS: We examined the expression of all Wnt ligands and their receptors and the activity of Wnt signaling pathways in visceral adipose tissue from wild-type mice and two lines of adiponectin-transgenic mice. The effects of adiponectin were also investigated in cultured 3T3-L1 cells. RESULTS: The Wnt5b, Wnt6, Frizzled 6 (Fzd6), and Fzd9 genes were up-regulated in both lines of transgenic mice, whereas Wnt1, Wnt2, Wnt5a, Wnt9b, Wnt10b, Wnt11, Fzd1, Fzd2, Fzd4, Fzd7, and the Fzd coreceptor low-density-lipoprotein receptor-related protein 6 (Lrp6) were reduced. There was no difference in total β-catenin levels in whole-cell extracts, non-phospho-β-catenin levels in nuclear extracts, or mRNA levels of β-catenin target genes, indicating that hyperadiponectinemia did not affect canonical Wnt signaling. In contrast, phosphorylated calcium/calmodulin-dependent kinase II (p-CaMKII) and phosphorylated Jun N-terminal kinase (p-JNK) were markedly reduced in adipose tissue from the transgenic mice. The adipose tissue of the transgenic mice consisted of many small cells and had increased expression of adiponectin, whereas cyclooxygenase-2 expression was reduced. Wnt5b expression was elevated in preadipocytes of the transgenic mice and decreased in diet-induced obese mice, suggesting a role in adipocyte differentiation. Some Wnt genes, Fzd genes, and p-CaMKII protein were down-regulated in 3T3-L1 cells cultured with a high concentration of adiponectin. CONCLUSION: Chronic hyperadiponectinemia selectively modulated the expression of Wnt ligands, Fzd receptors and LRP coreceptors accompanied by the inhibition of the Wnt/Ca(2+) and JNK signaling pathways, which may be involved in the altered adipocyte cellularity, endogenous adiponectin production, and anti-inflammatory action induced by hyperadiponectinemia

Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p.

The genetic background that predisposes the Japanese population to type 2 diabetes is largely unknown. Therefore, we conducted a 10-cM genome-wide scan for type 2 diabetes traits in the 359 affected individuals from 159 families, yielding 224 affected sib-pairs of Japanese origin. Nonparametric multipoint linkage analyses performed in the whole population showed one suggestive linked region on 11p13-p12 (maximum logarithm of odds score [MLS] 3.08, near Pax6) and seven potentially linked regions (MLS >1.17) at 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 15q13-q21, and 20q12-q13 (near the gene for hepatocyte nuclear factor-4alpha [HNF-4alpha]). Subset analyses according to maximal BMI and early age at diagnosis added suggestive evidence of linkage with type 2 diabetes at 7p22-p21 (MLS 3.51), 15q13-q21 (MLS 3.91), and 20q12-q13 (MLS 2.32). These results support previous indication for linkage found on chromosome 3q, 15q, and 20q in other populations and identifies two new potential loci on 7p and 11p that may confer genetic risk for type 2 diabetes in the Japanese population

Analysis of the canonical Wnt signaling pathway in adipose tissue from wild-type mice and adiponectin-transgenic mice at the age of 20 weeks.

<p>(A) Western blot analysis of total β-catenin in whole-cell extracts and non-phosphorylated (active form) β-catenin in nuclear extracts. (B) Relative protein levels of total β-catenin in whole-cell extracts and non-phospho-β-catenin in nuclear extracts of adipose tissue from transgenic mice shown as ratios to those of wild-type mice (n = 5, each). (C) mRNA expression of c-Myc (<i>Myc</i>) and cyclin D1 (<i>Ccnd1</i>) genes in transgenic mice shown as ratios to wild-type mice (n = 10, each). Means and SD.</p

Analysis of the Wnt ligand family and their receptors in adipose tissue from wild-type mice and adiponectin-transgenic mice.

<p>mRNA levels of the Wnt ligand family (A), Frizzled receptors (B), non-Fzd Wnt receptors (C) and coreceptors (D) in adipose tissue from line 11 (closed bars) and line 13 (open bars) of male adiponectin-transgenic mice. Data are shown as ratios to wild-type C57BL/6 mice at the age of 20 weeks (n = 6–10, for each group). mRNA levels were determined by quantitative real-time RT-PCR and normalized to <i>Gapdh</i> mRNA. Means and SD, *p<0.05, **p<0.01 vs. wild-type mice.</p