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OBJECTIVE--Adiponectin is an important adipocytokine that improves insulin action and reduces atherosclerotic processes. The plasma adiponectin level is paradoxically reduced in obese individuals, but the underlying mechanism is unknown. This [...]

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, being activated during states of low energy charge. Hypothalamic AMPK activity is altered by hormonal and metabolic signals and mediates the feeding response. To determine the effect of diabetes on hypothalamic AMPK activity, we assayed this activity in streptozotocin (STZ)-induced diabetic rats. Compared with control rats, STZ-induced diabetic rats had significant hyperphagia and weight loss. Hypothalamic AMPK phosphorylation and [alpha]2-AMPK activity were higher and acetyl-CoA carboxylase activity was lower in diabetic rats than in control rats. Chronic insulin treatment or suppression of hypothalamic AMPK activity completely prevented diabetes-induced changes in food intake as well as in hypothalamic AMPK activity and mRNA expression of neuropeptide Y and proopiomelanocortin. Plasma leptin and insulin levels were profoundly decreased in diabetic rats. Intracerebroventricular administration of leptin and insulin reduced hyperphagia and the enhanced hypothalamic AMPK activity in diabetic rats. These data suggest that leptin and insulin deficiencies in diabetes lead to increased hypothalamic AMPK activity, which contributes to the development of diabetic hyperphagia., Diabetes is characterized by altered fuel metabolism due to relative or absolute deficiency of insulin. Individuals with uncontrolled diabetes commonly experience hyperphagia (1), which makes glycemic control more difficult. Several [...]

Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)α and PPAR-γ stimulation on the development of diabetes in obese diabetes-prone OLETF rats. Chronic administration of a PPAR-α agonist (0.5% [wt/wt] fenofibrate) or a PPAR-γ agonist (3 mg * kg-1 * day-1 rosiglitazone) completely prevented the development of glycosuria. Pancreatic islets from untreated OLETF rats underwent sequential hypertrophy and atrophy, which was completely prevented by chronic fenofibrate treatment. In contrast, rosiglitazone treatment did not affect islet hypertrophy at earlier stages but prevented β-cell atrophy at later stages. Fenofibrate treatment decreased body weight and visceral fat, whereas rosiglitazone treatment increased body weight. Despite the opposite effects on adiposity, both drugs were equally effective in improving insulin actions in skeletal muscle. Furthermore, both drugs significantly decreased the triglyceride content in the soleus muscle and pancreatic islets. The present study demonstrates that the PPAR-α agonist fenofibrate prevents the development of diabetes in OLETF rats by reducing adiposity, improving peripheral insulin action, and exerting beneficial effects on pancreatic β-cells., Increasing evidence suggests lipid that accumulation in nonadipose tissues, such as skeletal muscle and pancreatic islet, is causally related to the development of type 2 diabetes in obese individuals (1,2) [...]

ABSTRACTAlthough macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3deletion in pink1knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7KO mice showed significantly lower expression of Nlrp3in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.Abbreviations:ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.

Groundwater is the main source of water for beverages, and its quality varies depending on extraction location; this is particularly the case in regions with complex geology, topography, and multiple forms of land use. Thus, it is important to determine a suitable groundwater extraction location based on intended water use and the related water quality standards. In this study, deep neural network (DNN) models and GIS data relating to groundwater quality were applied to estimate potential maps of Gangwon Province in South Korea, where groundwater is frequently extracted for drinking purposes. These maps specify areas where the groundwater quality is conducive for being used as mineral water and water for brewing coffee (hereafter referred as “coffee water”). Sensitivity analysis identified how inputs were sensitive to model estimation and showed that land‐use variables were the most sensitive. The importance of each variable quantified how good or bad its region is for the desired groundwater. The overall features of importance were similar between mineral water and coffee water. However, with differences in hydrogeological units, carbonate rock was a variable of high positive importance for mineral water; metamorphic rock was its equivalent for coffee water. Our results offer a potential map of desired groundwater quality in the absence of a detailed understanding of the underlying hydrochemical processes governing groundwater quality. Additionally, the development of such a potential mapping model can help to determine the appropriate development area of groundwater for their respective purposes.

ObjectiveLipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.DesignWild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).ResultsHFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1but not Sms2was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1expression, and Sms1knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.ConclusionSMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

Type 2 diabetes and asthma share a common pathophysiology: “chronic inflammation.” However, it is unclear whether patients with type 2 diabetes are at increased risk of asthma.

Studies have shown an association between diabetes and Parkinson disease (PD). The retina is a part of the central nervous system; it was proposed that diabetic retinopathy (DR) and PD share common pathophysiology of dopamine deficiency. However, no epidemiologic studies have investigated the relationship between these two diseases.

A neutral loss scan of 141, corresponding to a phosphoethanolamine head group, has been commonly used for the determination of various glycerophosphoethanolamine species in complex lipid mixtures. However, the neutral loss of 141 Da is not a major fragmentation pathway in the collision-induced dissociation (CID) of ethanolamine plasmalogens in the positive-ion mode. Thus, the use of the neutral loss scan of 141 can be problematic to observe all possible ethanolamine phospholipids in biological samples. Ethanolamine plasmalogens could easily form adducts with Ag(I) ions, and the CID of Ag(I)-adducted ethanolamine plasmalogens provided abundant head group loss of 141 with higher collision energy. Thus, all ethanolamine plasmalogens could be identified from a neutral loss scan of 141 after Ag(I) adduction. This novel approach could be a useful diagnostic tool to observe most of the possible glycerophosphoethanolamine species in complex lipid mixtures.

The groundwater of Jeju Island (Republic of Korea) is vulnerable to contamination because its aquifers are mainly composed of highly permeable geological units and its agricultural fields are often exposed to excessive use of predominantly synthetic fertilizers. In the Gosan area of Jeju Island, we investigated nitrate contamination in both a perched aquifer above an impermeable clay bed and the regional groundwater beneath this aquitard. The δ18O and δD values indicate that the perched groundwater is recharged by local precipitation, whereas the regional groundwater is recharged mainly by regional flow from an adjacent mountainous region. The perched groundwater contained very high NO3–N concentrations of up to 87 mg/L. The isotopic composition of nitrate in the perched groundwater showed that synthetic fertilizers applied in high excesses of crop N needs were the main cause of aquifer pollution. Elevated nitrate concentrations were also observed in the regional groundwater especially after precipitation events. Concentration and isotopic data revealed that the inflow of shallow perched groundwater along the poorly cemented or uncemented annulus of regional groundwater wells was one of the main reasons for the nitrate contamination observed in the regional groundwater. In both aquifers, δ15N and δ18O values showed that the sources of nitrate were derived from synthetic fertilizers that had been recycled in the soil zone by nitrification and in some portions of the perched aquifer (dissolved oxygen concentrations <2 mg/L) indicated that denitrification occurred locally.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.

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