Takayuki Hanamoto

Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice

Androgen reduces fat mass, although the underlying mechanisms are unknown. Here, we examined the effect of testosterone on heat production and mitochondrial biogenesis. Testosterone‐treated mice exhibited elevated heat production. Treatment with testosterone increased the expression level of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC1α), ATP5B and Cox4 in skeletal muscle, but not that in brown adipose tissue and liver. mRNA levels of genes involved in mitochondrial biogenesis were elevated in skeletal muscle isolated from testosterone‐treated male mice, but were down‐regulated in androgen receptor deficient mice. These results demonstrated that the testosterone‐induced increase in energy expenditure is derived from elevated mitochondrial biogenesis in skeletal muscle.

Effects of phorbol ester‐sensitive PKC (c/nPKC) activation on the production of adiponectin in 3T3‐L1 adipocytes

PPARγ plays a key role in adipocyte specific gene expression. In this study, we assessed the effects of phorbol ester (TPA)‐sensitive PKC (c/nPKC) activation on the expression of adipocyte specific genes and inflammation related genes. Treatment with both TPA and TNFα decreased mRNA levels of PPARγ, aP2, LPL and adiponectin. TNFα, but not TPA, increased IL‐6 and MCP‐1 mRNA levels, Next, we investigated the effects of ligands which activate c/nPKC. Insulin and angiotensin II (AII), but not high glucose, reduced PPARγ, aP2 and adiponectin mRNA levels. AII‐induced suppression of these genes was restored in the presence of Go6976, a specific c/nPKC inhibitor, and candesartan, an AII receptor blocker. The effect of reduced insulin was prevented by Go6976 and LY294002, a specific PI 3‐kinase inhibitors. Our results indicate that activation of c/nPKC could debilitate and/or might deteriorate insulin sensitivity in vivo, through the reduction of PPARγ and adiponectin expression in adipocyte.

Surgical treatment of multiple spinal canal stenoses associated with vitamin D-resistant rickets

We describe a 44-year-old woman who was diagnosed in childhood with vitamin D-resistant rickets, and who had paraparesis due to multiple spinal canal stenoses between C5 and L1 with ossification of the posterior longitudinal ligament and the yellow ligament. She was treated surgically with laminoplasty of the C2 through C7 levels and laminectomy from T8 through T11. Four months later, she underwent anterior fusion using an ilium graft by thoracotomy from the T12 to L1 levels. Six months after surgery, her symptoms improved. After 5 years, and with oral vitamin D, no progression of symptoms has been observed.

Effect of Dehydroepiandrosterone on Insulin Sensitivity and Adipocyte Growth in Otsuka Long-Evans Tokushima-Fatty Rats

Dehydroepiandrosterone (DHEA) (1) is the major adrenal androgen of young adults. However, serum concentration of DHEA in 60 yearold men shows a gradual decrease, when compared with young men aged 25-30 years old. This decrease occurs as the incidence of atherosclerosis (2), obesity (3), and diabetes increases (4), suggesting that administration of DHEA may protect against the development of these disorders. Previously, we reported that in vitro DHEA treatment increased glucose uptake and activation of PI 3-kinase in native rat adipocytes (5). Protein kinase C (PKC) is a family of serine/threonine kinases, which play key functions in cellular signal transduction. Three categories of PKC, conventional, novel, and atypical PKCs, have been described depending on their mechanisms of activation. Moreover, it is known that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is the hub of many signaling pathways, which phosphorylate many downstream kinases of phosphatidylinositol 3-kinase (PI 3-kinase), such as Akt kinase, S6 kinase and PKC. Previous studies suggested that atypical PKC (aPKC/) isoforms are required for insulin stimulation of glucose uptake (6), and PDK1 is necessary for activation of aPKCs (7). It has been reported that DHEA treatment reduces fat accumulation and protects against insulin resistance via an increase in PI 3-kinase after immunoprecipitation with insulin receptor substrate-1 (IRS-1) in male rats (8). We have investigated the in-vitro and in-vivo effects of DHEA on insulin-induced glucose uptake in adipocytes of Otsuka Log-Evans Tokushima fatty (OLETF) (9) and LETO rats. Moreover, we have shown the DHEA-induced glucose uptake by activation of PI 3-kinase/atypaical PKC siganlling without association with IRS-1 (10). In vivo treatment with DHEA affects on a decrease of adipose tissue via downregulation of peroxisome proliferator-activated receptor  (PPAR) expression (11). Based on above results, we have searched more precise mechanism of DHEA-induced amelioration of insulin sensitivity and clinical application of DHEA in diabetic animal models and human male adults.