Yun Hee Lee

A heuristic for vehicle fleet mix problem using tabu search and set partitioning

The vehicle fleet mix problem is a special case of the vehicle routing problem where customers are served by a heterogeneous fleet of vehicles with various capacities. An efficient heuristic for determining the composition of a vehicle fleet and travelling routes was developed using tabu search and by solving set partitioning problems. Two kinds of problems have appeared in the literature, concerning fixed cost and variable cost, and these were tested for evaluation. Initial solutions were found using the modified sweeping method. Whenever a new solution in an iteration of the tabu search was obtained, optimal vehicle allocation was performed for the set of routes, which are constructed from the current solution by making a giant tour. Experiments were performed for the benchmark problems that appeared in the literature and new best-known solutions were found.

Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.

De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis.

Recent advance in brown adipose physiology and its therapeutic potential

Brown adipose tissue (BAT) is a specialized thermoregulatory organ that has a critical role in the regulation of energy metabolism. Specifically, energy expenditure can be enhanced by the activation of BAT function and the induction of a BAT-like catabolic phenotype in white adipose tissue (WAT). Since the recent recognition of metabolically active BAT in adult humans, BAT has been extensively studied as one of the most promising targets identified for treating obesity and its related disorders. In this review, we summarize information on the developmental origin of BAT and the progenitors of brown adipocytes in WAT. We explore the transcriptional control of brown adipocyte differentiation during classical BAT development and in WAT browning. We also discuss the neuronal control of BAT activity and summarize the recently identified non-canonical stimulators of BAT that can act independently of β-adrenergic stimulation. Finally, we review new findings on the beneficial effects of BAT activation and development with respect to improving metabolic profiles. We highlight the therapeutic potential of BAT and its future prospects, including pharmacological intervention and cell-based therapies designed to enhance BAT activity and development.

Hepatoprotective effect of licorice, the root of Glycyrrhiza uralensis Fischer, in alcohol-induced fatty liver disease

BackgroundOur previous study suggested that licorice has anti-inflammatory activity in lipopolysaccharide-stimulated microglial cells and anti-oxidative activity in tert-butyl hydroperoxide–induced oxidative liver damage. In this study, we evaluated the effect of licorice on chronic alcohol-induced fatty liver injury mediated by inflammation and oxidative stress.MethodsRaw licorice was extracted, and quantitative and qualitative analysis of its components was performed by using LC–MS/MS. Mice were fed a liquid alcohol diet with or without licorice for 4xa0weeks.ResultsWe have standardized 70xa0% fermented ethanol extracted licorice and confirmed by LC-MS/MS as glycyrrhizic acid (GA), 15.77u2009±u20090.34xa0μg/mg; liquiritin (LQ), 14.55u2009±u20090.42xa0μg/mg; and liquiritigenin (LG), 1.34u2009±u20090.02xa0μg/mg, respectively. Alcohol consumption increased serum alanine aminotransferase and aspartate aminotransferase activities and the levels of triglycerides and tumor necrosis factor (TNF)-α. Lipid accumulation in the liver was also markedly induced, whereas the glutathione level was reduced. All these alcohol-induced changes were effectively inhibited by licorice treatment. In particular, the hepatic glutathione level was restored and alcohol-induced TNF-α production was significantly inhibited by licorice.ConclusionTaken together, our data suggests that protective effect of licorice against alcohol-induced liver injury may be attributed to its anti-inflammatory activity and enhancement of antioxidant defense.

Sex differences in sympathetic innervation and browning of white adipose tissue of mice

BackgroundThe higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.MethodsEffects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15xa0days.ResultsWe found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.ConclusionsCollectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.

Additive association of vitamin D insufficiency and sarcopenia with low femoral bone mineral density in noninstitutionalized elderly population: the Korea National Health and Nutrition Examination Surveys 2009–2010

SummaryVitamin D insufficiency and sarcopenia are crucial risk factors for osteoporosis. In a study of noninstitutionalized elderly subjects, we investigated the simultaneous effect of vitamin D and sarcopenia on bone mineral density (BMD) and found that sarcopenia was associated with low BMD in the femur, especially in those with suboptimal vitamin D levels.IntroductionAlthough vitamin D insufficiency and sarcopenia are prevalent in the elderly population worldwide, their possible influence on BMD has not been determined. We aimed to investigate the different effect of vitamin D insufficiency and sarcopenia on BMD in the elderly Korean population.MethodsIndividuals aged 60 or older were selected from those who participated in the Fourth and Fifth Korea National Health and Nutrition Examination Surveys conducted in 2009 and 2010; 1,596 males and 1,886 females were analyzed. Appendicular skeletal muscle mass (ASM) and BMD were assessed by dual-energy X-ray absorptiometry; serum 25-hydroxyvitamin D [25(OH)D] and a panel of clinical and laboratory parameters were also measured.ResultsThe study population was divided into four groups according to their vitamin D and sarcopenic status. BMD in total femur and in the femoral neck but not the lumbar spine was markedly decreased in sarcopenic subjects with vitamin D insufficiency [25(OH)Du2009<u200920xa0ng/ml] comparing to other groups, regardless of gender. Multivariable linear regression models showed that BMD was significantly associated with ASM and high daily calcium intake as well as conventional risk factors such as age, body mass index (BMI), and history of fracture. Independent predictors for low femur BMD included sarcopenia, low daily calcium intake, low 25(OH)D levels, age, and BMI.ConclusionsThese data showed that an association between vitamin D insufficiency and low BMD was more prominent in elderly subjects with sarcopenia.

Phenolics and neolignans isolated from the fruits of Juglans mandshurica Maxim. and their effects on lipolysis in adipocytes

Juglans mandshurica Maxim. (Juglandaceae) is a traditional folk medicine used for treatment of dermatosis and to relieve aches in Korea and China. In this study, eight compounds, along with six known compounds, were isolated from the fruit of J.xa0mandshurica. Among the six known compounds, the absolute configuration of two compounds were determined. The structures of compounds were determined on the basis of extensive spectroscopic methods, including 1D and 2D NMR and CD spectroscopic data. All isolated compounds were tested for their lipolytic activities in differentiated adipocytes using C3H10T1/2 mouse embryonic fibroblasts. Among them, 2-(4-formyl-2-methoxyphenoxy)-propan-1,3-diol and 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-propanediol exhibited the most potent lipolytic activities.

Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response

It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF)-α levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH) level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol.

Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease

Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis

Transient inflammation in adipose tissue triggers Jak-TGFβ signaling to promote beige adipocyte differentiation. Committing progenitors to adipogenesis Promoting the “browning” of white fat has been proposed as a strategy to combat obesity. Beige adipocytes, which are intermediate between fat-storing white adipocytes and thermogenic brown adipocytes, can emerge from the differentiation of adipocyte progenitors in adipose tissue in response to β3-adrenergic stimulation. Using primary human and mouse cells and ex vivo mouse models, Babaei et al. (see also the Focus by Sun et al.) found that the Jak family of kinases promoted the commitment of adipocyte progenitors to beige adipogenesis. Through the downstream transcription factor Stat3, Jak inhibited TGFβ signaling and prevented adipocyte progenitors from differentiating into smooth muscle cells. β3-Adrenergic stimulation of lipolysis, which transiently triggers inflammation, induced the production of the cytokines IL-6 and IL-11, which activated the Jak/Stat3 pathway. These results delineate a pathway that is activated by transient inflammation in adipose tissue that steers adipocyte progenitors toward differentiation into a thermogenically active form of fat. The transient activation of inflammatory networks is required for adipose tissue remodeling including the “browning” of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.