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\"What drives success in Asia? How did the pioneers do what they did, how are they planning their succession? After six seasons of Channel NewsAsia's Power List Asia, with 73 high-powered guests, over 26,000 manhours of pre- and post-production and 130,000 airmiles, comes Power Talk. Distilling the very best and most memorable conversations with various head honchos, Karen Lam sits down (not on television this time) to compile the best business ideas, personal philosophies, attitudes and intriguing stories into common themes of leadership and entrepreneurship in Asia. Featuring more than 20 Powerlisters and a range of topics such as crisis management, brand building, expanding westward and succession planning, Power Talk is a must-read for any Asian entrepreneur on the cusp of that next league\"-- Provided by publisher.

Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis through a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β-klotho. Administration of FGF21 to rodents or non-human primates causes considerable pharmacological benefits on a cluster of obesity-related metabolic complications, including a reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, cardiovascular disorders and non-alcoholic steatohepatitis (NASH). However, native FGF21 is unsuitable for clinical use owing to poor pharmacokinetic and biophysical properties. A large number of long-acting FGF21 analogues and agonistic monoclonal antibodies for the FGFR1–β-klotho receptor complexes have been developed. Several FGF21 analogues and mimetics have progressed to early phases of clinical trials in patients with obesity, type 2 diabetes mellitus and NASH. In these trials, the primary end points of glycaemic control have not been met, whereas substantial improvements were observed in dyslipidaemia, hepatic fat fractions and serum markers of liver fibrosis in patients with NASH. The complexity and divergence in pharmacology and pathophysiology of FGF21, interspecies variations in FGF21 biology, the possible existence of obesity-related FGF21 resistance and endogenous FGF21 inactivation enzymes represent major obstacles to clinical implementation of FGF21-based pharmacotherapies for metabolic diseases.Fibroblast growth factor 21 (FGF21) confers considerable pharmacological benefits on a cluster of obesity-related metabolic complications when administered to preclinical models. This Review discusses FGF21 analogues and mimetics and highlights their efficacy in preclinical models and clinical trials. The challenges in developing FGF21-based therapeutics are also considered.

Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment.

The global prevalence of non‐alcoholic fatty liver disease (NAFLD) is rising, along with the epidemic of diabesity. NAFLD is present in >70% of individuals with type 2 diabetes. Although the mutually detrimental relationship between NAFLD and type 2 diabetes has been well established, a multitude of recent studies have further shown that type 2 diabetes is closely linked to the development of cirrhosis, hepatocellular carcinoma, liver‐related morbidity and mortality. In contrast, NAFLD also negatively impacts type 2 diabetes both in terms of its incidence and related adverse clinical outcomes, including cardiovascular and chronic kidney diseases. In response to these global health threats, clinical care pathways for NAFLD and guidelines for metabolic dysfunction‐associated fatty liver disease have been developed. Several antidiabetic agents have been evaluated for their potential hepatic benefits with promising results. Furthermore, type 2 diabetes patients are increasingly represented in clinical trials of novel therapeutics for NAFLD. However, despite the wealth of knowledge in NAFLD and type 2 diabetes, lack of awareness of the disease and the potential weight of this problem remains a major challenge, especially among clinicians who are outside the field of hepatology and gastroenterology. This review therefore aimed to provide all diabetes care providers with a summary of the latest evidence that supports NAFLD as an emerging diabetic complication of increasing importance, and to present the current recommendations, focusing on the assessment and therapeutic strategies, on the management of NAFLD among type 2 diabetes patients. This review aimed to provide all diabetes care providers with a summary of the latest evidence that supports non‐alcoholic fatty liver disease as an emerging diabetes complication of increasing importance. It also presents the current recommendations, focusing on the assessment and therapeutic strategies, on the management of non‐alcoholic fatty liver disease among patients with type 2 diabetes.

Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans Xinmei Zhang 1 2 , Dennis C.Y. Yeung 1 2 , Michal Karpisek 3 , David Stejskal 4 , Zhi-Guang Zhou 8 , Feng Liu 5 6 , Rachel L.C. Wong 1 2 , Wing-Sun Chow 1 2 , Annette W.K. Tso 1 2 , Karen S.L. Lam 1 2 and Aimin Xu 1 2 7 1 Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China 2 Research Centre of Heart, Brain, Hormone, and Healthy Aging, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China 3 Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic 4 Department of Laboratory Medicine, Sternberk Hospital, Sternberk, Czech Republic 5 Department of Biochemistry, UTHSTCSA, San Antonio, Texas 6 Department of Pharmacology, UTHSTCSA, San Antonio, Texas 7 Department of Pharmacology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China 8 Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, China Corresponding author: Aimin Xu or Karen S.L. Lam, Department of Medicine, University of Hong Kong, L8-43, New Laboratory Block, 21 Sassoon Road, Hong Kong, China. E-mail: amxu{at}hkucc.hku.hk and ksllam{at}hku.hk Abstract OBJECTIVE— Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship between its serum levels and various cardiometabolic parameters in humans. RESEARCH DESIGN AND METHODS— A newly developed immunoassay was used to measure serum FGF21 levels in 232 Chinese subjects recruited from our previous cross-sectional studies. The mRNA expression levels of FGF21 in the liver and adipose tissues were quantified by real-time PCR. RESULTS— Serum FGF21 levels in overweight/obese subjects were significantly higher than in lean individuals. Serum FGF21 correlated positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol, after adjusting for age and BMI. Logistic regression analysis demonstrated an independent association between serum FGF21 and the metabolic syndrome. Furthermore, the increased risk of the metabolic syndrome associated with high serum FGF21 was over and above the effects of individual components of the metabolic syndrome. Our in vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations in humans. CONCLUSIONS— FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. The paradoxical increase of serum FGF21 in obese individuals, which may be explained by a compensatory response or resistance to FGF21, warrants further investigation. A-FABP, adipocyte–fatty acid–binding protein ELISA, enzyme-linked immunosorbent assay FGF, fibroblast growth factor HOMA-IR, homeostasis model assessment index–insulin resistance IL, interleukin NCEP, National Cholesterol Education Program NGT, normal glucose tolerance OGTT, oral glucose tolerance test PPAR, peroxisome proliferator–activated receptor QUICKI, quantitative insulin sensitivity check index TNF-α, tumor necrosis factor-α Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 5 February 2008. DOI: 10.2337/db07-1476. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1476 . X.Z. and D.C.Y.Y. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 29, 2008. Received October 16, 2007. DIABETES

Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue. Although thyroid hormone (TH) has anti-obesity potential, systemic administration of TH causes severe adverse effects without obvious weight loss. Here, the authors show that adipose tissue-targeted delivery of TH with liposomes is a safe and efficient strategy to treat obesity and its related complications in mice.

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells Kenneth K.Y. Cheng 1 2 , Karen S.L. Lam 1 2 , Yu Wang 3 , Yu Huang 4 , David Carling 5 , Donghai Wu 6 , Chiwai Wong 6 and Aimin Xu 1 2 6 1 Department of Medicine, University of Hong Kong, Hong Kong, China 2 Research Center of Heart, Brain Hormone and Healthy Aging, University of Hong Kong, Hong Kong, China 3 Genome Research Center and Department of Biochemistry, University of Hong Kong, Hong Kong, China 4 Department of Physiology, Chinese University of Hong Kong, Hong Kong, China 5 Cellular Stress Group, Medical Research Council (MRC) Clinical Sciences Centre, Imperial College, U.K 6 Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Address correspondence and reprint requests to Aimin Xu, PhD, Department of Medicine, University of Hong Kong, L8-43, New Laboratory Block, 21 Sassoon Road, Hong Kong. E-mail: amxu{at}hkucc.hku.hk Abstract Adiponectin protects the vascular system partly through stimulation of endothelial nitric oxide (NO) production and endothelium-dependent vasodilation. The current study investigated the role of two recently identified adiponectin receptors, AdipoR1 and -R2, and their downstream effectors in mediating the endothelium actions of adiponectin. In human umbilical vein endothelial cells, adiponectin-induced phosphorylation of endothelial NO synthase (eNOS) at Ser 1177 and NO production were abrogated when expression of AdipoR1 and -R2 were simultaneously suppressed. Proteomic analysis demonstrated that the cytoplasmic tails of both AdipoR1 and -R2 interacted with APPL1, an adaptor protein that contains a PH (pleckstrin homology) domain, a PTB (phosphotyrosine-binding) domain, and a Leucine zipper motif. Suppression of APPL1 expression by RNA interference significantly attenuated adiponectin-induced phosphorylation of AMP-activated protein kinase (AMPK) at Thr 172 and eNOS at Ser 1177 , and the complex formation between eNOS and heat shock protein 90, resulting in a marked reduction of NO production. Adenovirus-mediated overexpression of a constitutively active version of AMPK reversed these changes. In db/db diabetic mice, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased compared with their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of AdipoR1 and -R2, mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation. AMPK, AMP-activated protein kinase eNOS, endothelial nitric oxide synthase GFP, green fluorescent protein HSP, heat shock protein HUVEC, human umbilical vein endothelial cell l-NAME, Nω-nitro-l-arginine methyl ester PI, phosphoinositide RNAi, RNA interference Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 7 February 2007. DOI: 10.2337/db06-1580. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1580 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 29, 2007. Received November 12, 2006. DIABETES

Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.

Fibroblast growth factor (FGF) 21 is an endocrine factor actively involved in glucose and lipid metabolism in rodents. However, little is known about its physiological function and regulation in humans. This study investigated the diurnal changes in circulating FGF21 concentrations and their association with other metabolic markers in both obese and lean individuals. A total of 36 volunteers were assigned to 2 groups. One group received 3 standardized meals and another group was fasted for 24 h. Blood samples were drawn every 30 min throughout a 24-h period. Circulating FGF21 concentrations were measured with an in-house chemiluminescence immunoassay. The effects of fatty acids on hepatic production of FGF21 were determined by using real-time PCR. In both the fasting and standardized meals groups, circulating FGF21 began to rise at midnight, reaching a peak in the early morning and then declining to basal concentrations early in the afternoon. Baseline concentrations of circulating FGF21 were much higher in obese individuals than in lean individuals (P < 0.05). However, the magnitude of the nocturnal rise in circulating FGF21 was significantly blunted in obese individuals. The 24-h oscillatory pattern of circulating FGF21 resembled that of free fatty acids and cortisol, but was opposite to the patterns of insulin and glucose. Unsaturated fatty acids induced time-dependent expression of FGF21 mRNA in human hepatocytes. These findings support the role of FGF21 as an important metabolic regulator that integrates the circadian rhythm with energy homeostasis in humans. Diurnal rhythms of circulating FGF21 could be partly caused by the oscillation of free fatty acids.

Adipose tissue is a highly heterogeneous endocrine organ. The heterogeneity among different anatomical depots stems from their intrinsic differences in cellular and physiological properties, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, insulin sensitivity, hormonal control, thermogenic ability and vascularization. Additional factors that influence adipose tissue heterogeneity are genetic predisposition, environment, gender and age. Under obese condition, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. For instance, individuals with central obesity are more susceptible to developing diabetes and cardiovascular complications, whereas those with peripheral obesity are more metabolically healthy. This review summarizes the clinical and mechanistic evidence for the depot-specific differences that give rise to different metabolic consequences, and provides therapeutic insights for targeted treatment of obesity. Obesity: Understanding white fat tissues Investigations are needed into the variety of white fat tissue deposits in the body and their influence on obesity-related health problems. Aimin Xu and colleagues at the University of Hong Kong reviewed current understanding of white adipose (fat) tissue and how it behaves in different parts of the body. Adipose tissue is known to be highly diverse in composition, with differences in its cellular and physiological properties depending on how large the fat cells become and where they accumulate in the body. People with ‘central obesity’—extensive fat deposits in the abdominal region—are more likely to develop diabetes and heart problems, for example. The researchers call for further research examining the associations between fat deposits and risks of obesity-related health problems, in the hope that therapies targeting adipose tissues might become a possibility.