Publications

BACKGROUND: This study examined gender differences in the relationship between living alone and depressive symptoms in elderly Korean adults and the variables that influence this relationship.

METHODS: We conducted a secondary analysis using fourth-wave data from adults 65 yr of age or older who participated in the Korean Longitudinal Study of Aging. Depressive symptoms were measured using the 10-item short-form of the Center for Epidemiological Studies Depression Scale. Multiple logistic regression analyses were used.

RESULTS: After controlling for the factors of formal and informal social activities, financial support from children, employment, activities of daily living, instrumental activities of daily living, self-rated health, frequency of meals, and gender, living alone (AOR=1.45, 95% CI =1.09-1.93, P=0.010) was an independent risk factor that contributed to depressive symptoms in late life. Living alone was more likely to elevate depressive symptoms in older women but not in older men.

CONCLUSION: Gender differences in the depressive effect of living alone in late life may differ across diverse cultures.

Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin's ability to inhibit feeding but did not counter leptin's ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin's effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.

Adipose tissue is a specialized organ that synthesizes and stores fat. During adipogenesis, Rho and Rho-associated kinase (ROCK) 2 are inactivated, which enhances the expression of pro-adipogenic genes and induces the loss of actin stress fibers. Furthermore, pan ROCK inhibitors enhance adipogenesis in 3T3-L1 cells. Here, we show that KD025 (formerly known as SLx-2119), a ROCK2-specific inhibitor, suppresses adipogenesis in 3T3-L1 cells partially through a ROCK2-independent mechanism. KD025 downregulated the expression of key adipogenic transcription factors PPARγ and C/EBPα during adipogenesis in addition to lipogenic factors FABP4 and Glut4. Interestingly, adipogenesis was blocked by KD025 during days 1 3 of differentiation; after differentiation terminated, lipid accumulation was unaffected. Clonal expansion occurred normally in KD025-treated cells. These results suggest that KD025 could function during the intermediate stage after clonal expansion. Data from depletion of ROCKs showed that KD025 suppressed cell differentiation partially independent of ROCK's activity. Furthermore, no further loss of actin stress fibers emerged in KD025-treated cells during and after differentiation compared to control cells. These results indicate that in contrast to the pro-adipogenic effect of pan-inhibitors, KD025 suppresses adipogenesis in 3T3-L1 cells by regulating key pro-adipogenic factors. This outcome further implies that KD025 could be a potential anti-adipogenic/obesity agent.

OBJECTIVE: Insulin resistance is a major risk factor for type 2 diabetes. ApolipoproteinJ (ApoJ) has been implicated in altered pathophysiologic states including cardiovascular and Alzheimer's disease. However, the function of ApoJ in regulation of glucose homeostasis remains unclear. This study sought to determine whether serum ApoJ levels are associated with insulin resistance in human subjects and if they change after interventions that improve insulin sensitivity.

METHODS: Serum ApoJ levels and insulin resistance status were assessed in nondiabetic (ND) and type 2 diabetic (T2D) subjects. The impacts of rosiglitazone or metformin therapy on serum ApoJ levels and glucose disposal rate (GDR) during a hyperinsulinemic/euglycemic clamp were evaluated in a separate cohort of T2D subjects. Total ApoJ protein or that associated with the HDL and LDL fractions was measured by immunoblotting or ELISA.

RESULTS: Fasting serum ApoJ levels were greatly elevated in T2D subjects (ND vs T2D; 100±8.3 vs. 150.6±8.5AU, P<0.0001). Circulating ApoJ levels strongly correlated with fasting glucose, fasting insulin, HOMA-IR, and BMI. ApoJ levels were significantly and independently associated with HOMA-IR, even after adjustment for age, sex, and BMI. Rosiglitazone treatment in T2D subjects resulted in a reduction in serum ApoJ levels (before vs. after treatment; 100±13.9 vs. 77±15.2AU, P=0.015), whereas metformin had no effect on ApoJ levels. The change in ApoJ levels during treatment was inversely associated with the change in GDR. Interestingly, ApoJ content in the LDL fraction was inversely associated with HOMA-IR.

CONCLUSION: Serum ApoJ levels are closely correlated with the magnitude of insulin resistance regardless of obesity, and decrease along with improvement of insulin resistance in response only to rosiglitazone in type 2 diabetes.

OBJECTIVE: Fructose malabsorption is a common digestive disorder in which absorption of fructose in the small intestine is impaired. An abnormality of the main intestinal fructose transporter proteins has been proposed as a cause for fructose malabsorption. However the underlying molecular mechanism for this remains unclear. In this study, we investigated whether carbohydrate response element-binding protein (ChREBP) plays a role in intestinal fructose absorption through the regulation of genes involved in fructose transport and metabolism and ion transport.

METHODS: Wild type (WT) and Chrebp knockout (KO) mice (6 or 8 weeks old) were fed a control diet (55% starch, 15% maltodextrin 10) or high-fructose diet (HFrD, 60% fructose, 10% starch) for 3-12 days. Body weight and food intake were measured, signs of fructose malabsorption were monitored, and the expression of genes involved in fructose transport/metabolism and ion transport was evaluated. Furthermore, transient transfection and chromatin immunoprecipitation were performed to show the direct interaction between ChREBP and carbohydrate response elements in the promoter of Slc2A5, which encodes the fructose transporter GLUT5.

RESULTS: Chrebp KO mice fed the control diet maintained a constant body weight, whereas those fed a HFrD showed significant weight loss within 3-5 days. In addition, Chrebp KO mice fed the HFrD exhibited a markedly distended cecum and proximal colon containing both fluid and gas, suggesting incomplete fructose absorption. Fructose-induced increases of genes involved in fructose transport (GLUT5), fructose metabolism (fructokinase, aldolase B, triokinase, and lactate dehydrogenase), and gluconeogenesis (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were observed in the intestine of WT but not of Chrebp KO mice. Moreover the Na+/H+ exchanger NHE3, which is involved in Na+ and water absorption in the intestine, was significantly decreased in HFrD-fed Chrebp KO mice. Consistent with this finding, the high-fructose diet-fed Chrebp KO mice developed severe diarrhea. Results of chromatin immunoprecipitation assays showed a direct interaction of ChREBP with the Glut5 promoter, but not the Nhe3 promoter, in the small intestine. Ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X activated the Glut5 promoter in Caco-2BBE cells.

CONCLUSIONS: ChREBP plays a key role in the dietary fructose transport as well as conversion into lactate and glucose through direct transcriptional control of genes involved in fructose transport, fructolysis, and gluconeogenesis. Moreover, ablation of Chrebp results in a severe diarrhea in mice fed a high-fructose diet, which is associated with the insufficient induction of GLUT5 in the intestine.

Obesity is a major risk factor for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and is closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity owing to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiological significance, hepatic ROCK1 was markedly upregulated in humans with fatty liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1/AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used antidiabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1/AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.

Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS inhibition completely abrogates macrophage accumulation and activation, proinflammatory cytokine overproduction, reactive astrogliosis, blood-brain-barrier permeability, and lipid accumulation in the ARC of obese mice. Moreover, central iNOS inhibition improves obesity-induced alterations in systemic glucose metabolism without affecting adiposity. Our findings suggest a critical role for hypothalamic macrophage-expressed iNOS in hypothalamic inflammation and abnormal glucose metabolism in cases of overnutrition-induced obesity.

Emerging data demonstrate that microglia activation plays a pivotal role in the development of hypothalamic inflammation in obesity. Early after the introduction of a high-fat diet, hypothalamic microglia undergo morphological, and functional changes in response to excessive dietary saturated fats. Initially the resident microglia are affected; however, as diet-induced obesity persists, bone marrow-derived myeloid cells gradually replace resident microglia. Genetic and pharmacological approaches aimed at dampening the inflammatory activity in the hypothalamus of experimental models of obesity have proven beneficial to correct the obese phenotype and improve metabolic abnormalities commonly associated with obesity. These approaches provide an experimental proof-of-concept that hypothalamic inflammation is central to the pathophysiology of obesity; understanding the details of the roles played by microglia in this process may help the development of preventive and therapeutic advances in the field. In this review, we discuss the potential mechanisms underlying hypothalamic microglial activation in high-fat induced obesity.

AIMS: Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown.

METHODS AND RESULTS: We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05).

CONCLUSION: Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.