Circulating miR-148a associates with sensitivity to adiponectin levels in human metabolic surgery for weight loss
OBJECTIVE:We sought to discover secreted biomarkers to monitor the recovery of physiological adiponectin levels with metabolic surgery, focusing on epigenetic changes that might predict adiponectin function. DESIGN/METHODS:We conducted a prospective observational study of patients undergoing metabolic surgery by Roux-en-Y gastric bypass (RYGB) for weight loss in a single center (IRB GHS # 1207-27). METHODS:All patients (n=33; 27 females; 6 males) signed informed consent. Metabolites, adiponectin, and miR-148a were measured in fasting plasma. We followed MIQE for transcript profiles. RESULTS:Patients lost on average 47Â±12% excess BMI (%EBMI) after 12 weeks. Adiponectin pre, post or delta [post minus pre] did not correlate with %EBMIL. A decrease in adiponectin following weight loss surgery was observed in a subset of patients, chi-square test of independence rejects the null hypotheses that the liver DNMT1 and delta adiponectin are independent (Chi-square statistics Ï‡2 38 = 6.9205, P= 0.00852, n=33), as well as miR-148a and delta adiponectin are independent (Chisquare statistics Ï‡2 40 = 9.6823, P= 0.00186, n=33). The presence of plasma miR-148a allows identification of patients that appear to be adiponectin insensitive at baseline. CONCLUSION/CONCLUSIONS:We combined the presence of plasma miR-148a, the concentration of total adiponectin and the expression of DNA methyltransferase 1 (DNMT1) in liver biopsy tissue to identify patients with non-physiological adiponectin. Weight loss and physical activity interventions complemented with the new method presented here could serve to monitor the physiological levels of adiponectin, thought to be important for long-term weight loss maintenance.
Celecoxib does not alter intestinal microbiome in a longitudinal diet-controlled study [Letter]
Noninvasive Detection of Inflammatory Changes in White Adipose Tissue by Label-Free Raman Spectroscopy
White adipose tissue inflammation (WATi) has been linked to the pathogenesis of obesity-related diseases, including type 2 diabetes, cardiovascular disease, and cancer. In addition to the obese, a substantial number of normal and overweight individuals harbor WATi, putting them at increased risk for disease. We report the first technique that has the potential to detect WATi noninvasively. Here, we used Raman spectroscopy to detect WATi with excellent accuracy in both murine and human tissues. This is a potentially significant advance over current histopathological techniques for the detection of WATi, which rely on tissue excision and, therefore, are not practical for assessing disease risk in the absence of other identifying factors. Importantly, we show that noninvasive Raman spectroscopy can diagnose WATi in mice. Taken together, these results demonstrate the potential of Raman spectroscopy to provide objective risk assessment for future cardiometabolic complications in both normal weight and overweight/obese individuals.
Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies
Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.
Basal Insulin Use in the Non-Critical Care Setting: Is Fasting Hypoglycemia Inevitable or Preventable? [Letter]
Mechanisms of obesity-induced gastrointestinal neoplasia
Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.
Tracking cellular metabolomics in lipoapoptosis- and steatosis-developing liver cells
Palmitate (PA) is known to induce reactive oxygen species (ROS) formation and apoptosis in liver cells, whereas concurrent treatment of oleate (OA) with PA predominately induces steatosis without ROS in liver cells. We previously reported that PA treatment induces the decoupling of glycolysis and tricarboxylic acid cycle (TCA cycle) fluxes, but OA co-treatment restored most metabolic fluxes to their control levels. However, the mechanisms by which metabolites are linked to metabolic fluxes and subsequent lipoapoptotic or steatotic phenotypes remain unclear. To determine the link, we used GC-MS-based polar and non-polar metabolic profiling in lipoapoptosis- or steatosis-developing H4IIEC3 hepatoma cells, to examine the metabolome at different time points after treatment with either PA alone (PA cells) or both PA and OA (PA/OA cells). Metabolic profiles revealed various changes in metabolite levels for TCA cycle intermediates, pentose phosphate pathway (PPP) intermediates, and energy storage metabolites between PA and PA/OA cells. For example, adenosine was markedly increased only in PA cells, whereas gluconate was increased in PA/OA cells. To assess the interaction among these metabolites, the metabolite-to-metabolite correlations were calculated and correlation networks were visualized. These correlation networks demonstrate that a dissociation among PPP metabolites was introduced in PA-treated cells, and this dissociation was restored in PA/OA-treated cells. Thus, our data suggest that abnormal PPP fluxes, in addition to increased adenosine levels, might be related to the decoupling of glycolysis and the resulting lipoapoptotic phenotype.
Ketogenic essential amino acids modulate lipid synthetic pathways and prevent hepatic steatosis in mice
BACKGROUND: Although dietary ketogenic essential amino acid (KAA) content modifies accumulation of hepatic lipids, the molecular interactions between KAAs and lipid metabolism are yet to be fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We designed a diet with a high ratio (E/N) of essential amino acids (EAAs) to non-EAAs by partially replacing dietary protein with 5 major free KAAs (Leu, Ile, Val, Lys and Thr) without altering carbohydrate and fat content. This high-KAA diet was assessed for its preventive effects on diet-induced hepatic steatosis and whole-animal insulin resistance. C57B6 mice were fed with a high-fat diet, and hyperinsulinemic ob/ob mice were fed with a high-fat or high-sucrose diet. The high-KAA diet improved hepatic steatosis with decreased de novo lipogenesis (DNL) fluxes as well as reduced expressions of lipogenic genes. In C57B6 mice, the high-KAA diet lowered postprandial insulin secretion and improved glucose tolerance, in association with restored expression of muscle insulin signaling proteins repressed by the high-fat diet. Lipotoxic metabolites and their synthetic fluxes were also evaluated with reference to insulin resistance. The high-KAA diet lowered muscle and liver ceramides, both by reducing dietary lipid incorporation into muscular ceramides and preventing incorporation of DNL-derived fatty acids into hepatic ceramides. CONCLUSION: Our results indicate that dietary KAA intake improves hepatic steatosis and insulin resistance by modulating lipid synthetic pathways.
The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling
Phosphoinositide 3-kinase (PI3K) plays a critical role in tumorigenesis, and the PI3K p85 regulatory subunit exerts both positive and negative effects on signaling. Expression of Pik3r1, the gene encoding p85, is decreased in human prostate, lung, ovarian, bladder, and liver cancers, consistent with the possibility that p85 has tumor suppressor properties. We tested this hypothesis by studying mice with a liver-specific deletion of the Pik3r1 gene. These mice exhibited enhanced insulin and growth factor signaling and progressive changes in hepatic pathology, leading to the development of aggressive hepatocellular carcinomas with pulmonary metastases. Liver tumors that arose exhibited markedly elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, along with Akt activation and decreased PTEN expression, at both the mRNA and protein levels. Together, these results substantiate the concept that the p85 subunit of PI3K has a tumor-suppressive role in the liver and possibly other tissues.
Effect of anaplerotic fluxes and amino acid availability on hepatic lipoapoptosis
To identify metabolic pathways involved in hepatic lipoapoptosis, metabolic flux analysis using [U-(13)C(5)]glutamine as an isotopic tracer was applied to quantify phenotypic changes in H4IIEC3 hepatoma cells treated with either palmitate alone (PA-cells) or both palmitate and oleate in combination (PA/OA-cells). Our results indicate that palmitate inhibited glycolysis and lactate dehydrogenase fluxes while activating citric acid cycle (CAC) flux and glutamine uptake. This decoupling of glycolysis and CAC fluxes occurred during the period following palmitate exposure but preceding the onset of apoptosis. Oleate co-treatment restored most fluxes to their control levels, resulting in steatotic lipid accumulation while preventing apoptosis. In addition, palmitate strongly increased the cytosolic NAD(+)/NADH ratio, whereas oleate co-treatment had the opposite effect on cellular redox. We next examined the influence of amino acids on these free fatty acid-induced phenotypic changes. Increased medium amino acids enhanced reactive oxygen species (ROS) generation and apoptosis in PA-cells but not in PA/OA-cells. Overloading the medium with non-essential amino acids induced apoptosis, but essential amino acid overloading partially ameliorated apoptosis. Glutamate was the most effective single amino acid in promoting ROS. Amino acid overloading also increased cellular palmitoyl-ceramide; however, ceramide synthesis inhibitors had no effect on measurable indicators of apoptosis. Our results indicate that free fatty acid-induced ROS generation and apoptosis are accompanied by the decoupling of glycolysis and CAC fluxes leading to abnormal cytosolic redox states. Amino acids play a modulatory role in these processes via a mechanism that does not involve ceramide accumulation.