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    Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet. Woods Angela,Williams Jennet R,Muckett Phillip J,Mayer Faith V,Liljevald Maria,Bohlooly-Y Mohammad,Carling David Cell reports AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma). 10.1016/j.celrep.2017.03.011
    Dietary Fructose Metabolism By Splanchnic Organs: Size Matters. Gonzalez Javier T,Betts James A Cell metabolism The initial metabolism of fructose is thought to primarily take place in the liver. Using stable isotope labeling combined with tissue and arterio-venous sampling, Jang et al. (2018) demonstrate that in mice, the small intestine is the primary site of fructose metabolism. This raises important questions about fructose handling in humans. 10.1016/j.cmet.2018.02.013
    Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver. Della Torre Sara,Mitro Nico,Meda Clara,Lolli Federica,Pedretti Silvia,Barcella Matteo,Ottobrini Luisa,Metzger Daniel,Caruso Donatella,Maggi Adriana Cell metabolism Sex impacts on liver physiology with severe consequences for energy metabolism and response to xenobiotic, hepatic, and extra-hepatic diseases. The comprehension of the biology subtending sex-related hepatic differences is therefore very relevant in the medical, pharmacological, and dietary perspective. The extensive application of metabolomics paired to transcriptomics here shows that, in the case of short-term fasting, the decision to maintain lipid synthesis using amino acids (aa) as a source of fuel is the key discriminant for the hepatic metabolism of male and female mice. Pharmacological and genetic interventions indicate that the hepatic estrogen receptor (ERα) has a key role in this sex-related strategy that is primed around birth by the aromatase-dependent conversion of testosterone into estradiol. This energy partition strategy, possibly the result of an evolutionary pressure enabling mammals to tailor their reproductive capacities to nutritional status, is most important to direct future sex-specific dietary and medical interventions. 10.1016/j.cmet.2018.05.021
    Dietary Fructose and Microbiota-Derived Short-Chain Fatty Acids Promote Bacteriophage Production in the Gut Symbiont Lactobacillus reuteri. Oh Jee-Hwan,Alexander Laura M,Pan Meichen,Schueler Kathryn L,Keller Mark P,Attie Alan D,Walter Jens,van Pijkeren Jan-Peter Cell host & microbe The mammalian intestinal tract contains a complex microbial ecosystem with many lysogens, which are bacteria containing dormant phages (prophages) inserted within their genomes. Approximately half of intestinal viruses are derived from lysogens, suggesting that these bacteria encounter triggers that promote phage production. We show that prophages of the gut symbiont Lactobacillus reuteri are activated during gastrointestinal transit and that phage production is further increased in response to a fructose-enriched diet. Fructose and exposure to short-chain fatty acids activate the Ack pathway, involved in generating acetic acid, which in turn triggers the bacterial stress response that promotes phage production. L. reuteri mutants of the Ack pathway or RecA, a stress response component, exhibit decreased phage production. Thus, prophages in a gut symbiont can be induced by diet and metabolites affected by diet, which provides a potential mechanistic explanation for the effects of diet on the intestinal phage community. 10.1016/j.chom.2018.11.016
    Dietary L-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut. Kitamoto Sho,Alteri Christopher J,Rodrigues Michael,Nagao-Kitamoto Hiroko,Sugihara Kohei,Himpsl Stephanie D,Bazzi Malak,Miyoshi Mao,Nishioka Tatsuki,Hayashi Atsushi,Morhardt Tina L,Kuffa Peter,Grasberger Helmut,El-Zaatari Mohamad,Bishu Shrinivas,Ishii Chiharu,Hirayama Akiyoshi,Eaton Kathryn A,Dogan Belgin,Simpson Kenneth W,Inohara Naohiro,Mobley Harry L T,Kao John Y,Fukuda Shinji,Barnich Nicolas,Kamada Nobuhiko Nature microbiology Metabolic reprogramming is associated with the adaptation of host cells to the disease environment, such as inflammation and cancer. However, little is known about microbial metabolic reprogramming or the role it plays in regulating the fitness of commensal and pathogenic bacteria in the gut. Here, we report that intestinal inflammation reprograms the metabolic pathways of Enterobacteriaceae, such as Escherichia coli LF82, in the gut to adapt to the inflammatory environment. We found that E. coli LF82 shifts its metabolism to catabolize L-serine in the inflamed gut in order to maximize its growth potential. However, L-serine catabolism has a minimal effect on its fitness in the healthy gut. In fact, the absence of genes involved in L-serine utilization reduces the competitive fitness of E. coli LF82 and Citrobacter rodentium only during inflammation. The concentration of luminal L-serine is largely dependent on dietary intake. Accordingly, withholding amino acids from the diet markedly reduces their availability in the gut lumen. Hence, inflammation-induced blooms of E. coli LF82 are significantly blunted when amino acids-particularly L-serine-are removed from the diet. Thus, the ability to catabolize L-serine increases bacterial fitness and provides Enterobacteriaceae with a growth advantage against competitors in the inflamed gut. 10.1038/s41564-019-0591-6
    Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses. Nagai Motoyoshi,Noguchi Ryotaro,Takahashi Daisuke,Morikawa Takayuki,Koshida Kouhei,Komiyama Seiga,Ishihara Narumi,Yamada Takahiro,Kawamura Yuki I,Muroi Kisara,Hattori Kouya,Kobayashi Nobuhide,Fujimura Yumiko,Hirota Masato,Matsumoto Ryohtaroh,Aoki Ryo,Tamura-Nakano Miwa,Sugiyama Machiko,Katakai Tomoya,Sato Shintaro,Takubo Keiyo,Dohi Taeko,Hase Koji Cell Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis. 10.1016/j.cell.2019.07.047