Publications

BACKGROUND: The aim of this study was to examine whether formal and informal social activities are associated with a lower risk of depression. Besides, we investigated which type of social activities may protect against late-life depression by gender using data from a population-based study of older Korean adults.

METHODS: Data for analysis were drawn from the 2010 Korean Longitudinal Study of Aging. Study sample included 3968 Korean adults aged ≥ 65 years. Depression was measured using the 10-item Center for Epidemiological Studies. Depression scale. Multivariate logistic regression analyses were used.

RESULTS: Among the informal activities, frequent contact by phone or letters with adult children is significantly associated with a lower risk of depression among older Korean adults, even after adjusting for potentially confounding factors. Face to face contact with close friends was negatively associated with depression in women, but not in men. Face to face contacts with adult children were not significantly associated with depression. All of formal social activities (attending religious activities, volunteering, and participating in alumni society or family councils, political or interest groups) were not significantly associated with depression in both men and women.

CONCLUSIONS: Informal social activities (contact by phone/letters with children and contact with friends) may have a greater impact on geriatric depression than formal social activities in this population. Researchers need to consider gender differences when examining the relationship between social activity and depression. More research is warranted to examine the direction of associations between particular types of social activities and late-life depression across time.

Chronic exercise training results in numerous skeletal muscle adaptations, including increases in insulin sensitivity and glycogen content. To understand the mechanism leading to increased muscle glycogen, we studied the effects of exercise training on glycogen regulatory proteins in rat skeletal muscle. Female Sprague Dawley rats performed voluntary wheel running for 1, 4 or 7 weeks. After 7 weeks of training, insulin-stimulated glucose uptake was increased in epitrochlearis muscle. As compared with sedentary control rats, muscle glycogen did not change after 1 week of training, but increased significantly after 4 and 7 weeks. The increases in muscle glycogen were accompanied by elevated glycogen synthase activity and protein expression. To assess the regulation of glycogen synthase, we examined its major activator, protein phosphatase 1 (PP1), and its major deactivator, glycogen synthase kinase (GSK)-3. Consistent with glycogen synthase activity, PP1 activity was unchanged after 1 week of training but significantly increased after 4 and 7 weeks of training. Protein expression of R(GL)(G(M)), another regulatory PP1 subunit, significantly decreased after 4 and 7 weeks of training. Unlike PP1 activity, GSK-3 phosphorylation did not follow the pattern of glycogen synthase activity. The   40% decrease in GSK-3α phosphorylation after 1 week of exercise training persisted until 7 weeks, and may function as a negative feedback mechanism in response to elevated glycogen. Our findings suggest that exercise training-induced increases in muscle glycogen content could be regulated by multiple mechanisms, including enhanced insulin sensitivity, glycogen synthase expression, allosteric activation of glycogen synthase, and PP1 activity.

Soshiho-tang (Xiao-chai-hu-tang in Chinese and Sho-saiko-to in Japanese) has been widely used for its various pharmacological effects, which include anti-inflammatory, antioxidant, antihepatic fibrosis, and antitumor properties. To evaluate the safety of Soshiho-tang water extract (SST), we tested its subchronic toxicity in male and female Crl:CD (SD) rats. Rats were orally treated with four different doses (0, 500, 1000, and 2000 mg/kg/day) of SST administered for 13 weeks. Mortality, clinical signs, body weight changes, food and water consumption changes, ophthalmology, urinalysis, hematological and biochemical parameters, gross findings, organ weights, and histological markers were monitored during the study. The SST treatment did not result in any toxicologically significant changes in mortality, clinical signs, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematological and serum biochemical parameters, gross findings, organ weights, or histopathology. Histological analysis did not show any liver or kidney alteration. We concluded that the 13-week repeated oral administration of SST did not cause any adverse effects in rats at dosage levels of ≤2000 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level was concluded to be 2000 mg/kg/day for both sexes.

Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling.

Normal leptin signaling is essential for the maintenance of body weight homeostasis. Proopiomelanocortin- and agouti-related peptide (AgRP)-producing neurons play critical roles in regulating energy metabolism. Our recent work demonstrates that deletion of Rho-kinase 1 (ROCK1) in the AgRP neurons of mice increased body weight and adiposity. Here, we report that selective loss of ROCK1 in AgRP neurons caused a significant decrease in energy expenditure and locomotor activity of mice. These effects were independent of any change in food intake. Furthermore, AgRP neuron-specific ROCK1-deficient mice displayed central leptin resistance, as evidenced by impaired Signal Transducer and Activator of Transcription 3 activation in response to leptin administration. Leptin's ability to hyperpolarize and decrease firing rate of AgRP neurons was also abolished in the absence of ROCK1. Moreover, diet-induced and genetic forms of obesity resulted in reduced ROCK1 activity in murine arcuate nucleus. Of note, high-fat diet also impaired leptin-stimulated ROCK1 activity in arcuate nucleus, suggesting that a defect in hypothalamic ROCK1 activity may contribute to the pathogenesis of central leptin resistance in obesity. Together, these data demonstrate that ROCK1 activation in hypothalamic AgRP neurons is required for the homeostatic regulation of energy expenditure and adiposity. These results further support previous work identifying ROCK1 as a key regulator of energy balance and suggest that targeting ROCK1 in the hypothalamus may lead to development of antiobesity therapeutics.

The Ser/Thr Rho kinase 1 (ROCK1) is known to have major roles in a wide range of cellular activities, including those involved in tumour metastasis and apoptosis. Here we identify an indispensable function of ROCK1 in metabolic stress-induced autophagy. Applying a proteomics approach, we characterize Beclin1, a proximal component of the phosphoinositide 3-kinase class III lipid-kinase complex that induces autophagy, as an interacting partner of ROCK1. Upon nutrient deprivation, activated ROCK1 promotes autophagy by binding and phosphorylating Beclin1 at Thr119. This results in the specific dissociation of the Beclin1-Bcl-2 complex without affecting the Beclin1-UVRAG interaction. Conversely, inhibition of ROCK1 activity increases Beclin1-Bcl-2 association, thus reducing nutritional stress-mediated autophagy. Genetic knockout of ROCK1 function in mice also leads to impaired autophagy as evidenced by reduced autophagosome formation. These results show that ROCK1 acts as a prominent upstream regulator of Beclin1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy.

Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem. Elucidating the mechanisms behind the metabolic dysfunctions associated with obesity is of high priority. The metabolic function of Rho-kinase (Rho-associated coiled-coil-containing kinase; ROCK) has been the subject of a great deal of investigation in metabolic-related diseases. It appears that inhibition of ROCK activity is beneficial for the treatment of a wide range of cardiovascular-related diseases. However, recent studies with genetic models of ROCK demonstrate that ROCK plays a positive role in insulin and leptin signaling. Here we discuss the newly identified functions of ROCK in regulating glucose and energy metabolism, with particular emphasis on metabolic actions of insulin and leptin.

BACKGROUND: Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms.

METHODS AND FINDINGS: Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs.

CONCLUSIONS: Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes.

BACKGROUND: The role of pentraxin-3 (PTX3) in the development of insulin resistance is still not clear. We aimed to test 1) whether circulating PTX3 levels are associated with insulin resistance and 2) whether changes in PTX3 levels after the physical activity are associated with changes in insulin resistance.

METHODS: Fifty-seven overweight or obese children (39 boys, 18 girls; age: 12.04±0.82y, BMI: 26.5±1.2 kg/m²) participated in the study. All participants were housed together and their amount of physical activity (1823.5±1.34 kcal/day) and food intake (1882±68.8 kcal/day) were tightly controlled.

RESULTS: Circulating PTX3 levels at baseline were negatively associated with fasting insulin (r=-.336, p=0.012) and homeostasis model assessment of insulin resistance (HOMA-IR) (r=-.334, p=0.014) even after adjustment for BMI and Tanner stage. The degree of change in PTX3 levels notably associated with changes in fasting insulin (r=-.280, p=0.035) and HOMA-IR (r=-.281, p=.034) in response to the physical activity intervention. Subgroup analysis further indicates that HOMA-IR was improved more in subjects whose PTX3 levels were increased compared with subjects who PTX3 levels were decreased (HOMA-IR delta: -2.33±1.3 vs -1.46±0.70, p=0.004).

CONCLUSION: PTX3 is negatively associated with insulin resistance and associated with changes in insulin resistance induced by physical activity in overweight and obese children.