China has entered the era of obesity. Data from China Noncommunicable Disease (NCD) Surveillance 2010 have shown that one in three Chinese adults had either central or general obesity. Meanwhile, the epidemic of childhood obesity may weigh on China’s future. Obesity affects virtually all ages and socioeconomic groups and significantly contributes to the rocket-rising incidence of NCDs, including type 2 diabetes,cardiovasculardiseases,andcertain forms of cancer, which is worrisome for a country with a population of 1.37 billion. The huge demographic pressure, unbalanced economic development, unmet social diversity, and childhood obesity epidemic have all created tough challenges for the Chinese government to fight against obesity. Prevention and control strategies must be comprehensive and should include proactive approaches: reducing health disparity through healthcare reform and development, protecting parental and childhood health, enhancing education on a healthy lifestyle, implementing awareness and detection programs for genetically susceptible individuals, and early interventions targeting high-risk population. To efficiently halt the obesity epidemic, the main focus should be placed on children and adolescents. The national research supporting systems should encourage biomedical scientists to explore the pathogenesis of obesity and develop safe and effective novel anti-obesity drugs/procedures toward gut microbes, brown fat, and genetic targets in regulatory network of metabolism. International cooperation is of key importance in basic research and translational studies. It is tough, but with hope. Move It and Lose It

Adipositas stellt ein Gesundheitsproblem dar, das zurzeit mehr als 20 Prozent der deutschen Bevölkerung betrifft. Sie repräsentiert einen entscheidenden Risikofaktor für die Entwicklung adipositasassoziierter Erkrankungen und es ist zu erwarten, dass es bei einer weiteren Entwicklung der derzeitigen Inzidenz erstmalig im Jahre 2020 zu einer Abnahme der Lebenserwartung kommen wird. Nichtsdestotrotz sind die nachhaltigen und langfristigen therapeutischen Optionen bei der Adipositas derzeit enttäuschend.

Mutations in single genes and environmental interventions can extend healthy lifespan in laboratory model organisms. Some of the mechanisms involved show evolutionary conservation, opening the way to using simpler invertebrates to understand human ageing. Forkhead transcription factors have been found to play a key role in lifespan extension by alterations in the insulin/IGF pathway and by dietary restriction. Interventions that extend lifespan have also been found to delay or ameliorate the impact of ageing-related pathology and disease, including cancer. Understanding the mode of action of forkheads in this context will illuminate the mechanisms by which ageing acts as a risk factor for ageing-related disease, and could lead to the development of a broad-spectrum, preventative medicine for the diseases of ageing.

Insulin (IN) crosses the blood brain barrier by a receptor-mediated transport. However, less than 1% of peripheral injected IN reaches the CNS. Clinically, the association of altered glucose metabolism and neurodegenerative diseases has been described. Insulin-receptor(IR)-substrate-2-knockout-mice, as model of IN resistance and type 2 diabetes, display tau hyperphosphorylation. Hyperphosphorylated tau is a major component of tangles which were found in neurodegenerative conditions i.e. M. Alzheimer. To address, whether peripheral hyperinsulinemia influences cerebral IN signaling and contributes to tau hyperphosphorylation in vivo, we injected 0.01U (low dose group, LD) and 4U (high dose group, HD) IN into the inferior cava vein of anesthetized C57BL/6 mice and harvested brain tissue at 0,5,10,15,20min after injection. We investigated Akt-activity, IR-, Erk1/2-, GSK-3β- and Foxo1-phosphorylation as well as Ser202 and Thr231 tau phosphorylation. Blood glucose rose slightly after 5min and remained above baseline until 20min (LD&HD), excluding artifacts due to hypoglycemia. Injection of 0.01U IN led to a rapidly increased IR tyrosine phosphorylation within 5min (1.5fold, p≤0.01, n=10). Akt-activity increased 5min after injection with a maximum at 10min (2.8fold). GSK-3β phosphorylation increased within 10min (1.9fold, p≤0.05, n=11) and up to 2fold after 20min. Immunostainings of IN stimulated brains using pFoxo1 antibodies revealed a cytoplasmic neuronal staining in hypothalamus, thalamus, cortex and hippocampus. The LD group showed an increased Ser202 tau phosporylation 5min after injection, reaching significance after 15min (1.4fold, p≤0.01, n=10). Thr231 phosphorylation (LD&HD) remained unchanged. Injecting 4U IN revealed a further increase of Ser202 tau phosphorylation up to 2fold after 15min (p≤0.05, n=4) indicating a correlation between tau phosphorylation and peripheral IN levels. We conclude that peripherally injected IN leads to a rapid IR signal transduction in the CNS and contributes to a site-specific tau phosphorylation.

Patients with insulin resistance and/or type 2 diabetes have a 5-fold increased coronary risk and cardiovascular mortality rate. Therefore, it is a current issue of discussion that arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors, which might belong to a syndrome that is caused by decreased insulin sensitivity. Insulin resistance is associated with specific alterations of lipid metabolism. Typically there are elevated triglyceride levels and low HDL cholesterol levels. Furthermore, this dyslipoproteinemia is associated with alterations in the composition of LDL particles possibly increasing their atherogenicity. The relation between insulin resistance and arterial hypertension is much more evident in patients with obesity. Recently, a general change in our understanding of the pathogenesis of obesity has emerged, realizing that the fat cell is not only a passive reservoir of triglycerides, but might be active in the synthesis and secretion of endocrine active peptides. e.g., leptin or angiotensinogen. Concerning a possible molecular link between insulin resistance, atherosclerosis and obesity, we focus in our research on questions looking for a molecular link between cholesterol metabolism, insulin action, and obesity.Sterol regulatory element binding proteins (SREBPs) are transcription factors, which are regulated by the intracellular content of cholesterol. Recently, we could show, that these SREBPs are also modulated by insulin and growth factors like PDGE Interestingly, one of the SREBPs (SREBP-lc) is identical to the transcription factor called ADD1 (adipocyte differentation determination factor 1). ADD 1 plays an essential role in mechanisms linked to adipocyte differentiation. Therefore, these transcription factors might be a gene regulatory convergence point not only for metabolic but also endocrine signals. In an attempt to identify genetic defects of insulin resistance, we have characterized various postreceptor defects of insulin affecting the MAP-kinase cascade. This intracellular signaling cascade couples the insulin receptor to major gene regulatory events including the transcription factors mentioned above. These studies provide evidence that single gene defects in a signaling step affecting various gene regulatory events might be associated with a very complex clinical phenotype.