Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. NAFLD encompasses a whole spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The latter can lead to hepatocellular carcinoma. Furthermore, NASH is the most rapidly increasing indication for liver transplantation in western countries and therefore represents a global health issue. The pathophysiology of NASH is complex and includes multiple parallel hits. NASH is notably characterized by steatosis as well as evidence of hepatocyte injury and inflammation, with or without fibrosis. NASH is frequently associated with type 2 diabetes and conditions associated with insulin resistance. Moreover, NASH may also be found in many other endocrine diseases such as polycystic ovary syndrome, hypothyroidism, male hypogonadism, growth hormone deficiency or glucocorticoid excess, for example. In this review, we will discuss the pathophysiology of NASH associated with different endocrinopathies.
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Ruixin Hu, Yanting Yuan, Chaolong Liu, Ji Zhou, Lixia Ji, and Guohui Jiang
In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic β-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.
Nese Cinar and Alper Gurlek
Adipose tissue secretes a variety of active biological substances, called adipocytokines, that act in an autocrine, paracrine, and endocrine manner. They have roles in appetite control, thermogenesis, and thyroid and reproductive functions. All these molecules may lead to local and generalized inflammation, mediating obesity-associated vascular disorders including hypertension, diabetes, atherosclerosis, and insulin resistance. Thyroid dysfunction is associated with changes in body weight, thermogenesis, and energy expenditure. The connections between cardiovascular risk factors such as dyslipidemia, impaired glucose tolerance, insulin resistance, atherosclerosis, and thyroid dysfunction have been reported in several studies. The adipocytokines serve as causative or protective factors in the development of these disorders in the states of thyroid dysfunction. Abnormal levels of adipocytokines (adiponectin (ADP), leptin, resistin, vaspin, and visfatin) in hypo- and hyperthyroidism have been reported with controversial results. This review aims to update the implication of novel adipokines ADP, vaspin, and visfatin in thyroid dysfunction.
Simon Schimmack, Yongchao Yang, Klaus Felix, Markus Herbst, Yixiong Li, Miriam Schenk, Frank Bergmann, Thilo Hackert, and Oliver Strobel
Objective
Elevated pre-operative C-reactive protein (CRP) serum values have been reported to be associated with poor overall survival for patients with pancreatic neuroendocrine neoplasms (pNEN). The aim of this study was to identify mechanisms linking CRP to poor prognosis in pNEN.
Methods
The malignant properties of pNENs were investigated using the human pNEN cell-lines BON1 and QGP1 exposed to CRP or IL-6. Analyses were performed by ELISA, Western blot, flow cytometry and immunocytochemistry as well as invasion and proliferation assays. To compare cytokine profiles and CRP levels, 76 serum samples of pNEN patients were analyzed using Luminex technology. In parallel, the expression of CRP and growth signaling pathway proteins was assessed on cell lines and paraffin-embedded primary pNEN.
Results
In BON1 and QGP1 cells, inflammation (exposure to IL-6) significantly upregulated CRP expression and secretion as well as migratory properties. CRP stimulation of BON1 cells increased IL-6 secretion and invasion. This was accompanied by activation/phosphorylation of the ERK, AKT and/or STAT3 pathways. Although known CRP receptors – CD16, CD32 and CD64 – were not detected on BON1 cells, CRP uptake of pNEN cells was shown after CRP exposure. In patients, increased pre-operative CRP levels (≥5 mg/L) were associated with significantly higher serum levels of IL-6 and G-CSF, as well as with an increased CRP expression and ERK/AKT/STAT3 phosphorylation in pNEN tissue.
Conclusion
The malignant properties of pNEN cells can be stimulated by CRP and IL-6 promoting ERK/AKT/STAT pathways activation as well as invasion, thus linking systemic inflammation and poor prognosis.
Wenqi Yang, Ling Liu, Yuan Wei, Chunlu Fang, Fu Zhou, Jinbao Chen, Qinghua Han, Meifang Huang, Xuan Tan, Qiuyue Liu, Qiang Pan, Lu Zhang, Xiaojuan Lei, and Liangming Li
Objective
The protective effects of exercise against glucose dysmetabolism have been generally reported. However, the mechanism by which exercise improves glucose homeostasis remains poorly understood. The FGF21–adiponectin axis participates in the regulation of glucose metabolism. Elevated levels of FGF21 and decreased levels of adiponectin in obesity indicate FGF21–adiponectin axis dysfunction. Hence, we investigated whether exercise could improve the FGF21–adiponectin axis impairment and ameliorate disturbed glucose metabolism in diet-induced obese mice.
Methods
Eight-week-old C57BL/6J mice were randomly assigned to three groups: low-fat diet control group, high-fat diet group and high-fat diet plus exercise group. Glucose metabolic parameters, the ability of FGF21 to induce adiponectin, FGF21 receptors and co-receptor levels and adipose tissue inflammation were evaluated after 12 weeks of intervention.
Results
Exercise training led to reduced levels of fasting blood glucose and insulin, improved glucose tolerance and better insulin sensitivity in high-fat diet-induced obese mice. Although serum FGF21 levels were not significantly changed, both total and high-molecular-weight adiponectin concentrations were markedly enhanced by exercise. Importantly, exercise protected against high-fat diet-induced impaired ability of FGF21 to stimulate adiponectin secretion. FGF21 co-receptor, β-klotho, as well as receptors, FGFR1 and FGFR2, were upregulated by exercise. We also found that exercise inhibited adipose tissue inflammation, which may contribute to the improvement in the FGF21–adiponectin axis impairment.
Conclusions
Our data indicate exercise protects against high-fat diet-induced FGF21–adiponectin axis impairment, and may thereby exert beneficial effects on glucose metabolism.
Clara Odilia Sailer, Sophia Julia Wiedemann, Konrad Strauss, Ingeborg Schnyder, Wiebke Kristin Fenske, and Mirjam Christ-Crain
Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium ≥150 mmol/L) by hypertonic saline infusion. Copeptin – a marker indicating vasopressin activity – serum sodium and osmolality, plasma IL-8 and TNF-α were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-α levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.12, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.
W N H Koek, N Campos-Obando, B C J van der Eerden, Y B de Rijke, M A Ikram, A G Uitterlinden, J P T M van Leeuwen, and M C Zillikens
Background
Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age.
Methods
We used the laboratory values of serum calcium, phosphate and albumin from three different samples ( 2005, 2010 and 2014 years) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into three age groups: 1–17, 18–44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex.
Results
In all three samples there was a significant sex × age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found. In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups of 18–44 and ≥45 years. In women, serum calcium levels were significantly higher in the age group 1–17 and the age group ≥45 years compared to the 18–44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1–17 years and lowest in the group 18–44 years.
Conclusion
There are age- dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex- differences are not yet fully elucidated.
Tatsuya Kondo, Nobukazu Miyakawa, Sayaka Kitano, Takuro Watanabe, Rieko Goto, Mary Ann Suico, Miki Sato, Yuki Takaki, Masaji Sakaguchi, Motoyuki Igata, Junji Kawashima, Hiroyuki Motoshima, Takeshi Matsumura, Hirofumi Kai, and Eiichi Araki
Nonalcoholic fatty liver disease (NAFLD) is often accompanied by metabolic disorders such as metabolic syndrome and type 2 diabetes (T2DM). Heat shock response (HSR) is one of the most important homeostatic abilities but is deteriorated by chronic metabolic insults. Heat shock (HS) with an appropriate mild electrical stimulation (MES) activates HSR and improves metabolic abnormalities including insulin resistance, hyperglycemia and inflammation in metabolic disorders. To analyze the effects of HS + MES treatment on NAFLD biomarkers, three cohorts including healthy men (two times/week, n = 10), patients with metabolic syndrome (four times/week, n = 40), and patients with T2DM (n = 100; four times/week (n = 40) and two, four, seven times/week (n = 20 each)) treated with HS + MES were retrospectively analyzed. The healthy subjects showed no significant alterations in NAFLD biomarkers after the treatment. In patients with metabolic syndrome, many of the NAFLD steatosis markers, including fatty liver index, NAFLD-liver fat score, liver/spleen ratio and hepatic steatosis index and NAFLD fibrosis marker, aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, were improved upon the treatment. In patients with T2DM, all investigated NAFLD steatosis markers were improved and NAFLD fibrosis markers such as the AST/ALT ratio, fibrosis-4 index and NAFLD-fibrosis score were improved upon the treatment. Thus, HS + MES, a physical intervention, may become a novel treatment strategy for NAFLD as well as metabolic disorders.
Renea A Taylor, Jennifer Lo, Natasha Ascui, and Matthew J Watt
The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.
Ling Zhou, Ruixue Zhang, Shuangyan Yang, Yaguang Zhang, and Dandan Shi
Background:
Our previous study revealed that astragaloside IV (AS-IV) effectively improved gestational diabetes mellitus (GDM) by reducing hepatic gluconeogenesis. Due to the importance of placental oxidative stress, we further explored the protective role of AS-IV on placental oxidative stress in GDM.
Methods:
First, non-pregnant mice were orally administrated with AS-IV to evaluate its safety and effect. Then GDM mice were orally administered with AS-IV for 20 days and its effect on the symptoms of GDM, placental oxidative stress, secretions of inflammatory cytokines, as well as toll-like receptor 4 (TLR4)/NF-κB signaling pathway, were evaluated.
Results:
AS-IV had no adverse effect on non-pregnant mice. On the other hand, AS-IV significantly attenuated the GDM-induced hyperglycemia, glucose intolerance, insulin resistance, placental oxidative stress, productions of inflammatory cytokines and the activation of TLR4/NF-κB pathway.
Conclusion:
AS-IV effectively protected against GDM by alleviating placental oxidative stress and inflammation, in which TLR4/NF-κB might be involved.
