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Obesity predisposes to type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), but underlying mechanisms are incompletely understood. Potassium channel tetramerization domain-containing protein 17 (Kctd17) levels are increased in livers from obese mice and humans. In this study, we investigated the mechanism of increased Kctd17 and whether it is causal to obesity-induced metabolic complications. We transduced Rosa26-LSL-Cas9 knockin mice with AAV8-TBG-Cre (Control), AAV8-U6-Kctd17 sgRNA-TBG-Cre (L-Kctd17), AAV8-U6-Oga sgRNA-TBG-Cre (L-Oga), or AAV8-U6-Kctd17/Oga sgRNA-TBG-Cre (DKO). We fed mice a high-fat diet (HFD) and assessed for hepatic glucose and lipid homeostasis. We generated Kctd17 , O-GlcNAcase (Oga) , or Kctd17/Oga -knockout hepatoma cells by CRISPR-Cas9, and Kctd17 -directed antisense oligonucleotide to test therapeutic potential in vivo. We analyzed transcriptomic data from patients with NAFLD. Hepatocyte Kctd17 expression was increased in HFD-fed mice due to increased Srebp1c activity. HFD-fed L-Kctd17 or Kctd1 7 antisense oligonucleotide–treated mice show improved glucose tolerance and hepatic steatosis, whereas forced Kctd17 expression caused glucose intolerance and hepatic steatosis even in lean mice. Kctd17 induced Oga degradation, resulting in increasing carbohydrate response element-binding protein (Chrebp) protein, so concomitant Oga knockout negated metabolic benefits of hepatocyte Kctd17 deletion. In patients with NAFLD, KCTD17 messenger RNA was positively correlated with expression of Chrebp target and other lipogenic genes. Srebp1c-induced hepatocyte Kctd17 expression in obesity disrupted glucose and lipid metabolism by stabilizing Chrebp, and may represent a novel therapeutic target for obesity-induced T2D and NAFLD. Hepatocyte Kctd17 expression is increased in obesity, which predisposes to insulin resistance and liver fat accumulation. Blocking excess Kctd17 by either genetic or pharmacologic means reverses these pathologic processes, by decreasing Chrebp protein stability, a key factor that regulates both glucose and lipid metabolism. [ABSTRACT FROM AUTHOR]

Summary Mitochondrial activity is controlled by proteins encoded by both nuclear and mitochondrial DNA. Here, we identify Sirt7 as a crucial regulator of mitochondrial homeostasis. Sirt7 deficiency in mice induces multisystemic mitochondrial dysfunction, which is reflected by increased blood lactate levels, reduced exercise performance, cardiac dysfunction, hepatic microvesicular steatosis, and age-related hearing loss. This link between SIRT7 and mitochondrial function is translatable in humans, where SIRT7 overexpression rescues the mitochondrial functional defect in fibroblasts with a mutation in NDUFSI . These wide-ranging effects of SIRT7 on mitochondrial homeostasis are the consequence of the deacetylation of distinct lysine residues located in the hetero- and homodimerization domains of GABPβ1, a master regulator of nuclear-encoded mitochondrial genes. SIRT7-mediated deacetylation of GABPβ1 facilitates complex formation with GABPα and the transcriptional activation of the GABPα/GABPβ heterotetramer. Altogether, these data suggest that SIRT7 is a dynamic nuclear regulator of mitochondrial function through its impact on GABPβ1 function. [ABSTRACT FROM AUTHOR]

Summary Reverse cholesterol transport (RCT) is an antiatherogenic process in which excessive cholesterol from peripheral tissues is transported to the liver and finally excreted from the body via the bile. The nuclear receptor liver receptor homolog 1 (LRH-1) drives expression of genes regulating RCT, and its activity can be modified by different posttranslational modifications. Here, we show that atherosclerosis-prone mice carrying a mutation that abolishes SUMOylation of LRH-1 on K289R develop less aortic plaques than control littermates when exposed to a high-cholesterol diet. The mechanism underlying this atheroprotection involves an increase in RCT and its associated hepatic genes and is secondary to a compromised interaction of LRH-1 K289R with the corepressor prospero homeobox protein 1 (PROX1). Our study reveals that the SUMOylation status of a single nuclear receptor lysine residue can impact the development of a complex metabolic disease such as atherosclerosis. [ABSTRACT FROM AUTHOR]

Water quality monitoring programs often collect large amounts of data with limited attention given to the assessment of the dominant drivers of spatial and temporal water quality variations at the catchment scale. This study uses a multi-model approach: a) to identify the influential catchment characteristics affecting spatial variability in water quality; and b) to predict spatial variability in water quality more reliably and robustly. Tropical catchments in the Great Barrier Reef (GBR) area, Australia, were used as a case study. We developed statistical models using 58 catchment characteristics to predict the spatial variability in water quality in 32 GBR catchments. An exhaustive search method coupled with multi-model inference approaches were used to identify important catchment characteristics and predict the spatial variation in water quality across catchments. Bootstrapping and cross-validation approaches were used to assess the uncertainty in identified important factors and robustness of multi-model structure, respectively. The results indicate that water quality variables were generally most influenced by the natural characteristics of catchments (e.g., soil type and annual rainfall), while anthropogenic characteristics (i.e., land use) also showed significant influence on dissolved nutrient species (e.g., NO X , NH 4 and FRP). The multi-model structures developed in this work were able to predict average event-mean concentration well, with Nash-Sutcliffe coefficient ranging from 0.68 to 0.96. This work provides data-driven evidence for catchment managers, which can help them develop effective water quality management strategies. [Display omitted] • A multi-model approach reveals the key drivers for the spatial variation in water quality. • Catchment natural characteristics have the greatest impact on most constituents. • Land use has an important impact on dissolved nutrients. • Our results enable prediction of catchment water quality across space. A multi-model approach indicated that catchment natural characteristics have the greatest impact on water quality overall, but land use has an important impact on dissolved nutrients. [ABSTRACT FROM AUTHOR]

Background & Aims Obesity-induced nonalcoholic fatty liver disease (NAFLD) develops, in part, via excess insulin-stimulated hepatic de novo lipogenesis, which increases, paradoxically, in patients with obesity-induced insulin resistance. Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) terminates insulin signaling by dephosphorylating Akt; levels of PHLPP2 are reduced in livers from obese mice. We investigated whether loss of hepatic PHLPP2 is sufficient to induce fatty liver in mice, mechanisms of PHLPP2 degradation in fatty liver, and expression of genes that regulate PHLPP2 in livers of patients with NAFLD. Methods C57BL/6J mice (controls), obese db/db mice, and mice with liver-specific deletion of PHLPP2 ( L-PHLPP2 ) fed either normal chow or high-fat diet (HFD) were analyzed for metabolic phenotypes, including glucose tolerance and hepatic steatosis. PHLPP2-deficient primary hepatocytes or CRISPR/Cas9-mediated PHLPP2-knockout hepatoma cells were analyzed for insulin signaling and gene expression. We performed mass spectrometry analyses of liver tissues from C57BL/6J mice transduced with Ad-HA-Flag-PHLPP2 to identify posttranslational modifications to PHLPP2 and proteins that interact with PHLPP2. We measured levels of mRNAs by quantitative reverse transcription polymerase chain reaction in liver biopsies from patients with varying degrees of hepatic steatosis. Results PHLPP2-knockout hepatoma cells and hepatocytes from L-PHLPP2 mice showed normal initiation of insulin signaling, but prolonged insulin action. Chow-fed L-PHLPP2 mice had normal glucose tolerance but hepatic steatosis. In HFD-fed C57BL/6J or db/db obese mice, endogenous PHLPP2 was degraded by glucagon and PKA-dependent phosphorylation of PHLPP2 (at Ser1119 and Ser1210), which led to PHLPP2 binding to potassium channel tetramerization domain containing 17 (KCTD17), a substrate-adaptor for Cul3-RING ubiquitin ligases. Levels of KCTD17 mRNA were increased in livers of HFD-fed C57BL/6J or db/db obese mice and in liver biopsies patients with NAFLD, compared with liver tissues from healthy control mice or patients without steatosis. Knockdown of KCTD17 with small hairpin RNA in primary hepatocytes increased PHLPP2 protein but not Phlpp2 mRNA, indicating that KCTD17 mediates PHLPP2 degradation. KCTD17 knockdown in obese mice prevented PHLPP2 degradation and decreased expression of lipogenic genes. Conclusions In mouse models of obesity, we found that PHLPP2 degradation induced lipogenesis without affecting gluconeogenesis. KCTD17, which is up-regulated in liver tissues of obese mice and patients with NAFLD, binds to phosphorylated PHLPP2 to target it for ubiquitin-mediated degradation; this increases expression of genes that regulate lipogenesis to promote hepatic steatosis. Inhibitors of this pathway might be developed for treatment of patients with NAFLD. [ABSTRACT FROM AUTHOR]

[Display omitted] • In asynchronous climates, the forest growth response to rainfall is not well known. • Lagged relationship of forest growth to antecedent rainfall was explored. • Vegetation in the asynchronous climate have a long memory to the rainfall. • The memory of vegetation to rain could indicate soil/rooting depth across the landscape. The out-of-phase rainfall and temperature and deep root system make the sequential connection between past rainfall events, soil water storage, and forest growth response complicated and temporally extended in asynchronous climates with Mediterranean-type settings. Unfortunately, these location-specific deep-soil water stores are rarely measured due to logistic and financial constraints, especially in the forest. Therefore, at a large spatio-temporal scale, forest growth relationship to growth drivers is still unknown in these ecosystems, limiting our knowledge to understand the functioning of these forests and their links with hydrological processes. Although process-based water balance models can analyze vegetation growth response to the input climate forcing, they rely upon some significant assumptions regarding plants access to deep soil water storage. Thus, this study aims to understand how the out-of-phase rainfall events affect the current ecosystem growth response, represented by the observed Normalized Difference Vegetation Index (NDVI), across the landscape. We have used an empirical approach on long term observed data without any assumption on access to deep-soil water stores. We estimated time lags between forest growth and rainfall events using a lagged correlation analysis applied to monthly anomalies of NDVI and rainfall against their climatological averages over 2002–2018. The study found that the forests in asynchronous climates exhibit unexpectedly long (10–25 months) memory to rain, and this memory has a systematic pattern across the landscape, which we contend has highlighted three things: 1) the forest in the middle aridity (∼3–4.5) range are relatively more sensitive to changes in the short-term rainfall than the forest in lower (<3) and higher (>5) aridity regions, could be due to rapid depletion of relatively small soil water storage in between the storms, 2) the variable memory of forest to rain across the landscape can be an indicator of soil depth/rooting depth, and 3) the variable sized location specific antecedent rainfall windows can explain significant variability in forest growth status in asynchronous climates, thus these rainfall windows can be employed to forecast forest growth with a lead time (>4 months). [ABSTRACT FROM AUTHOR]

The commencement of SEAS5 model for operational seasonal climate forecasting by the European Centre for Medium-Range Weather Forecasts (ECMWF) is a new development. It replaces the ECMWF System 4, which had a large international community of seasonal climate forecast users. To assist potential users of SEAS5 forecasts, a systematic and detailed evaluation of forecast skill and reliability of climate variables over land areas is valuable. In this regional study, we evaluate SEAS5 performance in forecasting precipitation and daily minimum temperature (Tmin) and daily maximum temperature (Tmax) for the Australian continent, based on 36 years of re-forecast data. We evaluate forecasts after simple mean-corrections, and statistically calibrated forecasts using the Bayesian joint probability (BJP) modelling approach. We also provide a comparison with System 4. A new simpler and more efficient BJP algorithm is introduced to facilitate this study and support wider use of the algorithm in other applications. • Seasonal climate forecasts of the new ECMWF SEAS5 model are evaluated for Australia. • SEAS5 offers considerable skill for forecasting the coming month. • The skill drops significantly beyond one month forecast horizon. • A simpler and more efficient Bayesian joint probability (BJP) algorithm is introduced. • Forecasts are more skillful and reliable after calibration using the BJP algorithm. [ABSTRACT FROM AUTHOR]