News Roundup

Glucokinase activity in the arcuate nucleus regulates glucose intake

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Abstract

The brain relies on a constant supply of glucose, its primary fuel, for optimal function. A taste-independent mechanism within the CNS that promotes glucose delivery to the brain has been postulated to maintain glucose homeostasis; however, evidence for such a mechanism is lacking. Here, we determined that glucokinase activity within the hypothalamic arcuate nucleus is involved in regulation of dietary glucose intake. In fasted rats, glucokinase activity was specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Moreover, pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increased glucose ingestion, while decreased arcuate nucleus glucokinase activity reduced glucose intake. Pharmacologic targeting of potential downstream glucokinase effectors revealed that ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Additionally, altered glucokinase activity affected release of the orexigenic neurotransmitter neuropeptide Y in response to glucose. Together, our results suggest that glucokinase activity in the arcuate nucleus specifically regulates glucose intake and that appetite for glucose is an important driver of overall food intake. Arcuate nucleus glucokinase activation may represent a CNS mechanism that underlies the oft-described phenomena of the “sweet tooth” and carbohydrate craving.

Authors

Syed Hussain, Errol Richardson, Yue Ma, Christopher Holton, Ivan De Backer, Niki Buckley, Waljit Dhillo, Gavin Bewick, Shuai Zhang, David Carling, Steve Bloom, James Gardiner

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

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Abstract

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

Authors

Jenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, Katrin I. Andreasson

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

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Abstract

SCN5A encodes the α subunit of the major cardiac sodium channel Na_V1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A^E558X/+ pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A^E558X/+ hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A^E558X/+ pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.

Authors

David S. Park, Marina Cerrone, Gregory Morley, Carolina Vasquez, Steven Fowler, Nian Liu, Scott A. Bernstein, Fang-Yu Liu, Jie Zhang, Christopher S. Rogers, Silvia G. Priori, Larry A. Chinitz, Glenn I. Fishman

Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability

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Abstract

Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability.

Authors

Saleh AlAsiri, Sulman Basit, Michelle A. Wood-Trageser, Svetlana A. Yatsenko, Elizabeth P. Jeffries, Urvashi Surti, Deborah M. Ketterer, Sibtain Afzal, Khushnooda Ramzan, Muhammad Faiyaz-Ul Haque, Huaiyang Jiang, Michael A. Trakselis, Aleksandar Rajkovic

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet–induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota–associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.

Authors

Changtao Jiang, Cen Xie, Fei Li, Limin Zhang, Robert G. Nichols, Kristopher W. Krausz, Jingwei Cai, Yunpeng Qi, Zhong-Ze Fang, Shogo Takahashi, Naoki Tanaka, Dhimant Desai, Shantu G. Amin, Istvan Albert, Andrew D. Patterson, Frank J. Gonzalez