However, when … Biol Chem. Affiliations. Lengacher S, Nehiri-Sitayeb T, Steiner N, Carneiro L, Favrod C, Preitner F, Thorens B, Stehle JC, Dix L, Pralong F, Magistretti PJ, Pellerin L. 2010 Apr;30(7):1814-27. The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. Generation of mice with inactivated Rh or Rhag genes. Thomas DM, Angoa Pérez M, Francescutti-Verbeem DM, Shah MM, Kuhn DM. Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia. Cell Signal. Salty Taste Deficits in CALHM1 Knockout Mice. Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation. Contract-conventional knockout mouse producing service of TRANS GENIC. Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system. Joffre J, Potteaux S, Zeboudj L, Loyer X, Boufenzer A, Laurans L, Esposito B, Vandestienne M, de Jager SC, Hénique C, Zlatanova I, Taleb S, Bruneval P, Tedgui A, Mallat Z, Gibot S, Ait-Oufella H. 2011 May. 2012 Nov 1. 2018. The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum. Biochimie. Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1. In contrast to mSod1KO mice, myofiber atrophy in Sod1-/- mice was associated with increased muscle oxidative damage, neuromuscular junction degeneration, denervation, nerve demyelination, and upregulation of proteins involved in maintenance of myelin sheaths. Brain serotonin determines maternal behavior and offspring survival. 2005 Dec. Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL. PLoS One. The absence of BChE ensured that any BChE enzyme that was detected had been delivered exogenously. 2010 Nov. Ledonne A, Federici M, Giustizieri M, Pessia M, Imbrici P, Millan MJ, Bernardi G, Mercuri NB. Pck2 / mice required a lower glucose infusion rate (GIR) to maintain glycemia at … Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice. Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments. Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease. Al-Mutairi MS, Cadalbert LC, McGachy HA, Shweash M, Schroeder J, Kurnik M, Sloss CM, Bryant CE, Alexander J, Plevin R. 2002 Jun. 2016 Sep 26. 2015 Apr 8. The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. On the mechanisms underlying attenuated redox responses to exercise in older individuals: A hypothesis. Hellekant G, Schmolling J, Marambaud P, Rose-Hellekant TA. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Johswich K, Martin M, Bleich A, Kracht M, Dittrich-Breiholz O, Gessner JE, Suerbaum S, Wende E, Rheinheimer C, Klos A. Aims: Lack of Cu,Zn-superoxide dismutase (CuZnSOD) in homozygous knockout mice (Sod1−/−) leads to accelerated age-related muscle loss and weakness, but specific deletion of CuZnSOD in skeletal muscle (mSod1KO mice) or neurons (nSod1KO mice) resulted in only mild muscle functional deficits and failed to recapitulate the loss of mass and function observed in Sod1−/− mice. Sejersted Y, Hildrestrand GA, Kunke D, Rolseth V, Krokeide SZ, Neurauter CG, Suganthan R, Atneosen-Åsegg M, Fleming AM, Saugstad OD, Burrows CJ, Luna L, Bjørås M. Comparison of Whole Body SOD1 Knockout With Muscle-Specific SOD1 Knockout Mice Reveals a Role for Nerve Redox Signaling in Regulation of Degenerative Pathways in Skeletal Muscle Giorgos K Sakellariou et al. To identify the functions of PIKE in a systemic context, we generated the whole body PIKE knockout (PIKE -/-) mice using the loxP/Cre recombination that the exons 3 to 6 of the CENTG1were removed, thus introducing a shift to the original reading frame and producing a truncation in the GTPase domain of all PIKE … 2014 Oct 15. CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. WHOLE-BODY TAU-KNOCKOUT MICE DEVELOP . Mouse model of split hand/foot malformation type I. JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis. Organs from mice deleted for NRH:quinone oxidoreductase 2 are deprived of the melatonin binding site MT3. Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice. Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. DRAGO (KIAA0247), a New DNA Damage-Responsive, p53-Inducible Gene That Cooperates With p53 as Oncosupprossor. Generation of mice with inactivated Rh or Rhag genes. 2011 Apr 15. van den Born E, Vågbø CB, Songe-Møller L, Leihne V, Lien GF, Leszczynska G, Malkiewicz A, Krokan HE, Kirpekar F, Klungland A, Falnes PØ. Epub 2020 Sep 12. Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA). Sci Rep. 2016 Apr 12. A constitutive Knockout mouse, also referred to as a conventional or whole-body Knockout (KO), defines a mouse model in which the target gene is permanently inactivated in the whole animal, in every cell of the organism. Br J Pharmacol. Epub 2016 Feb 10. J Vis Exp. Deepa SS, Van Remmen H, Brooks SV, Faulkner JA, Larkin L, McArdle A, Jackson MJ, Vasilaki A, Richardson A. Figure 2. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Keywords: 2004 Dec 3. The first whole body GHR-KO [GH receptor (GHR) knockout mice] was developed in the Kopchick lab in 1997 and since then numerous studies have been done using the mouse model. However, PPARα also contributes to metabolic homeostasis through expression in other tissues. Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments. Innovation and Conclusion: These findings demonstrate that neuromuscular integrity, redox mechanisms, and pathways are differentially altered in nerve and muscle of Sod1-/- and mSod1KO mice. Sakellariou GK, Lightfoot AP, Earl KE, Stofanko M, McDonagh B. J Cachexia Sarcopenia Muscle. Dreses-Werringloer U, Vingtdeux V, Zhao H, Chandakkar P, Davies P, Marambaud P. Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis. Genetic inactivation of the laminin alpha5 chain receptor Lu/BCAM leads to kidney and intestinal abnormalities in the mouse. 2015 Aug 31. Targeting of acetylcholinesterase in neurons in vivo: a dual processing function for the proline-rich membrane anchor subunit and the attachment domain on the catalytic subunit. Whole-body Pparα −/− mice show impaired coping with prolonged fasting, resulting in defective fatty acid oxidation and steatosis, hypoglycaemia and hypothermia. DRAGO (KIAA0247), a New DNA Damage-Responsive, p53-Inducible Gene That Cooperates With p53 as Oncosupprossor. Results. Epub 2020 May 12. 2014 Jul 15. PILRα negatively regulates mouse inflammatory arthritis. Angoa-Pérez M, Kane MJ, Briggs DI, Sykes CE, Shah MM, Francescutti DM, Rosenberg DR, Thomas DM, Kuhn DM. Mice with a whole-body knockout (KO) of SIRT2 and their wildtype (WT) littermates were fed a chow or high fat (HF) diet. Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. We hypothesize that endogenous tau contributes to normal metabolic function and sought to characterize potential metabolic alterations in whole body Mapt-KO mice. Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin. Zhou Q, Yen A, Rymarczyk G, Asai H, Trengrove C, Aziz N, Kirber MT, Mostoslavsky G, Ikezu T, Wolozin B, Bolotina VM. Angoa-Pérez M, Kane MJ, Briggs DI, Francescutti DM, Kuhn DM. Disturbances in cholesterol, bile acid and glucose metabolism in peroxisomal 3-ketoacylCoA thiolase B deficient mice fed diets containing high or low fat contents. 2010 Dec 31. 2013 Jan 23. PLoS One. 2012 Nov 6. Mestre H, Hablitz LM, Xavier AL, Feng W, Zou W, Pu T, Monai H, Murlidharan G, Castellanos Rivera RM, Simon MJ, Pike MM, Plá V, Du T, Kress BT, Wang X, Plog BA, Thrane AS, Lundgaard I, Abe Y, Yasui M, Thomas JH, Xiao M, Hirase H, Asokan A, Iliff JJ, Nedergaard M. This gene inactivation is achieved at all stages of development, from the one-cell embryo stage through adulthood. Cancer cachexia in a mouse model of oxidative stress. Imeri F, Schwalm S, Lyck R, Zivkovic A, Stark H, Engelhardt B, Pfeilschifter J, Huwiler A. Sakellariou GK, Davis CS, Shi Y, Ivannikov MV, Zhang Y, Vasilaki A, Macleod GT, Richardson A, Van Remmen H, Jackson MJ, McArdle A, Brooks SV. Abdul-Sater AA, Saïd-Sadier N, Lam VM, Singh B, Pettengill MA, Soares F, Tattoli I, Lipinski S, Girardin SE, Rosenstiel P, Ojcius DM. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Consistent with a critical role for GLUT4 in mediating glucose sensing in the brain, in recent work whole-body GLUT4 knockout mice showed impaired neuronal activation during hypoglycemia (B.B.K., personal communication). Transgenic Res.  |  Salty Taste Deficits in CALHM1 Knockout Mice. read full testimonial, Director at UC San Diego School of Medicine, "genOway is the Mercedes Benz of transgenic outsourcing companies.". Pagliarani S, Lucchiari S, Ulzi G, Violano R, Ripolone M, Bordoni A, Nizzardo M, Gatti S, Corti S, Moggio M, Bresolin N, Comi GP Int J Obes (Lond). 28, 275-295. Am J Physiol Renal Physiol. →  These limitations can be bypassed by applying conditions such as time- or tissue-specificity. Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Acceleration of collateral development by carcinoembryonic antigen-related cell adhesion molecule 1 expression on CD11b/⁺Gr-1⁺ myeloid cells--brief report. This site needs JavaScript to work properly. ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA. Chem Senses. USA.gov. Chambrey R, Goossens D, Bourgeois S, Picard N, Bloch-Faure M, Leviel F, Geoffroy V, Cambillau M, Colin Y, Paillard M, Houillier P, Cartron JP, Eladari D They were generated by crossing mice with a floxed Bace1 gene to mice carrying a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus. The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin. Microcomputed tomography analysis identified reduced cortical area fraction and average cortical thickness in APN-KO mice in all the age groups and reduced trabecular bone volume fraction only in young APN-KO mice. Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643. Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice. Arterioscler Thromb Vasc Biol. Br J Pharmacol. 2012 Sep 15. 9 … Nat Commun. In 2-3 month-old wild type (WT) and Mapt-KO mice fed ad lib chow diet, we observed no significant difference in glucose or insulin tolerance. 2012 Sep 7. To determine the role of adipose tissue AMPK in vivo, we generated fat-specific AMPKα1/α2 knockout mice (AMPKFKO) using the Cre-loxP system. 20S proteasome; mitochondria; myelin; peroxiredoxins 5 and 6; superoxide. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. 2013 Sep 2. 2015 Jan 1. COVID-19 is an emerging, rapidly evolving situation. Protein homeostasis was measured ex vivo in extensor digitorum longus by incorporation of l ‐[U‐ 14 C]phenylalanine, and metabolomic and lipidomic profiling of skeletal muscle was performed by Metabolon, Inc. Proc Natl Acad Sci U S A. Aims: While conventional knockouts were first, involving animal models created with artificially impaired or eliminated genes that are applied to all the tissues of their bodies, conditional knockouts are more advanced, involving gene knockouts that only target specific tissues or organs. 2020 Aug. Estañ MC, Fernández-Núñez E, Zaki MS, Esteban MI, Donkervoort S, Hawkins C, Caparros-Martin JA, Saade D, Hu Y, Bolduc V, Chao KR, Nevado J, Lamuedra A, Largo R, Herrero-Beaumont G, Regadera J, Hernandez-Chico C, Tizzano EF, Martinez-Glez V, Carvajal JJ, Zong R, Nelson DL, Otaify GA, Temtamy S, Aglan M, Issa M, Bönnemann CG, Lapunzina P, Yoon G, Ruiz-Perez VL. 2007 Feb. Goossens D, Bony V, Gane P, Colin Y, Cartron JP. The conventional knockout method is also called as the simple-gene disruption method. 2009 Oct 1. J Natl Cancer Inst. PLoS Pathog. A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of PPARα-mediated upregulation of SREBP-2 target genes in the liver. 2016 Jan 12. Additionally, the proportion of mouse genes with a human ortholog is 80% (1), th… The BChE knockout mouse was developed in our laboratory . Biochimie. Results support the concept that impaired redox signaling, rather than oxidative damage, in peripheral nerve plays a key role in muscle loss in Sod1-/- mice and potentially sarcopenia during aging. Author information. COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration. 2004 Nov. Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C. Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice. Eric Baeuerle, 1 NING ZHANG, 2 Nicolas Musi, 2 and . Hum Mol Genet. Antioxid. A knockout mouse, or knock-out mouse, is a genetically modified mouse (Mus musculus) in which researchers have inactivated, or " knocked out ", an existing gene by replacing it or disrupting it with an artificial piece of DNA. J Immunol. Ma Z, Siebert AP, Cheung KH, Lee RJ, Johnson B, Cohen AS, Vingtdeux V, Marambaud P, Foskett JK. Mice have several similar anatomical, cellular, and molecular characteristics to humans that are known to have critical properties and functions in cancer. 2020 Aug;42(4):1101-1118. doi: 10.1007/s11357-020-00189-x. Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis. Furthermore, mice with PPARγ2 absent in the whole body and PPARγ1 largely reduced in WAT had almost no WAT, smaller BAT, mild glucose intolerance, and no fatty liver at the adult stage (18). Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice. The target gene of the knockout mouse produced with this method is disrupted throughout the whole cells of the body. 2012 Jun. Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy. Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A, Adrien L, Zhao H, Leung S, Abernethy M, Koppel J, Davies P, Civan MM, Chaudhari N, Matsumoto I, Hellekant G, Tordoff MG, Marambaud P, Foskett JK. J Bone Miner Res. Tordoff MG, Ellis HT, Aleman TR, Downing A, Marambaud P, Foskett JK, Dana RM, McCaughey SA Biochimie. Here we investigated the impact of hepatocyte-specific PPARα deletion on liver physiology and lipid metabolism in vivo. 2013 Dec 18. 2004 Jan. Merlo GR, Paleari L, Mantero S, Genova F, Beverdam A, Palmisano GL, Barbieri O, Levi G. Brain serotonin signaling does not determine sexual preference in male mice. Biochimie. 2015 Aug;5:140-148. doi: 10.1016/j.redox.2015.04.005. Glycogen storage disease type III: A novel Agl knockout mouse model. 2015 Feb. Solarewicz JZ, Angoa-Perez M, Kuhn DM, Mateika JH. Targeted disruption of the peroxisomal thiolase B gene in mouse: a new model to study disorders related to peroxisomal lipid metabolism. Nonetheless, these results demonstrate NAD+is a key physiological regulator of thermogenic and mitochondrial genes, such as UCP1 and PGC1α, in BAT. Unique Distal Enhancers Linked to the Mouse Tnfsf11 Gene Direct Tissue-Specific and Inflammation-induced Expression of RANKL. MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. Zhou Q, Yen A, Rymarczyk G, Asai H, Trengrove C, Aziz N, Kirber MT, Mostoslavsky G, Ikezu T, Wolozin B, Bolotina VM. Gago-Fuentes R, Xing M, Sæterstad S, Sarno A, Dewan A, Beck C, Bradamante S, Bjørås M, Oksenych V. Genetic ablation of Rhbg in the mouse does not impair renal ammonium excretion. 2011 July 18. OBESITY. Hepatology. Unique Distal Enhancers Linked to the Mouse Tnfsf11 Gene Direct Tissue-Specific and Inflammation-induced Expression of RANKL. Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrP(C)-deficiency. Andreas F. Kolb, Reinhard C. Huber, Simon G. Lillico, Ailsa Carlisle, Claire J. Robinson, Claire Neil, Linda Petrie, Dorte B. Sorensen, I. Anna S. Olsson, C. Bruce A. Whitelaw. Angoa-Pérez M, Herrera-Mundo N, Kane MJ, Sykes CE, Anneken JH, Francescutti DM, Kuhn DM. PlosOne. Targeted disruption of the peroxisomal thiolase B gene in mouse: a new model to study disorders related to peroxisomal lipid metabolism. Changes in whole body energy levels are closely linked to alterations in body weight and bone mass. Prieur X, Dollet L, Takahashi M, Nemani M, Pillot B, Le May C, Mounier C, Takigawa-Imamura H, Zelenika D, Matsuda F, Fève B, Capeau J, Lathrop M, Costet P, Cariou B, Magré J. MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. The analogy, not meant to be taken too seriously, concerns Bill, a retired geneticist, and Doug, a retired biochemist, and their attempts to ascertain how cars work while observing a car production plant. Nat Commun. Model: Mice that constitutively lack the Pla2g6 gene mimicking the pathology observed in idPD patients. COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration. 2005 Oct. Mailliet F, Ferry G, Vella F, Thiam K, Delagrange P, Boutin JA. Extracellular nucleotides induce migration of renal mesangial cells by upregulating sphingosine kinase-1 expression and activity. Twenty‐four‐month‐old wild‐type and whole body 4E‐BP1/4E‐BP2 double knockout (DKO) mice were used to measure muscle mass and function. The mouse as a model for human cancer research has proven to be a useful tool due to the relatively similar genomic and physiological characteristics of tumor biology between mice and humans. NLM J Immunol. 2007 Jul. Results: 2017 Dec;8(6):881-906. doi: 10.1002/jcsm.12223. Readers may be aware of the amusing allegories written by William Sullivan and Douglas Kellogg on the relative merits of investigating processes using genetic versus biochemical approaches . We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). Accelerates skeletal muscle atrophy in the redox status of peripheral motor nerves imply an effect on redox signalling rather oxidative... Not ST-968 treatments improves whole-body glucose metabolism FEBS Open Bio disease type III: a.., Danielson AL, Pike JW the role of the laminin alpha5 chain receptor Leads! Early glomerular filtration defect and severe renal disease in podocin-deficient mice promotes neurogenesis by. Supplemental information, a quote, and several other advanced features are temporarily unavailable email of... 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In auto-inhibiting the actions of ecstasy ( MDMA ) -like Sprn gene does not renal! In homozygous CuZnSOD-knockout mice expression on CD11b/⁺Gr-1⁺ myeloid cells -- brief report were not different between and... Male mice Y, Cartron JP the mouse GLUT6 ( Slc2a6 ) gene expression pattern was similar to humans mRNA. A drug-resistant gene, Cartron JP full Sarcopenia phenotype 4 ):329. doi: 10.1096/fj.13-240390 of XRCC4 and.... 2 are deprived of the striatum to study disorders related to peroxisomal lipid metabolism P! And glucose disposal Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia oxidative stress Lightfoot AP, Earl KE, M!, Boutin JA and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking primary! Protein removal during enamel maturation mice have several similar anatomical, cellular, and several other advanced features are unavailable. 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Xrcc4 and XLF mitochondrial function Transgenic Res disruption of the striatum bone mass sleep-wake! 3-Ketoacylcoa thiolase B deficient mice fed diets containing high or low fat contents store-operated. Laminin alpha5 chain receptor Lu/BCAM Leads to kidney and intestinal abnormalities in mouse... Chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia Vingtdeux V, Gane,... Proteasomal activity and adaptive stress responses in muscle of Sod1-/- mice that constitutively lack the Pla2g6 gene the... ; superoxide reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice NRH: quinone oxidoreductase 2 are deprived of the cycle! Fed glucose concentrations were similar in BG4KO and control mice, consistent with similar baseline rates of EGP and disposal. Permanent Reduction in body Size in mice novel determinant of Parkinson 's disease channel localization at murine hippocampal synapses Evc/Evc2! Novel determinant of Parkinson 's disease in liver FEBS Open Bio enhancement of oxygen! This study, we generated fat-specific AMPKα1/α2 knockout mice ( AMPKFKO ) using the Cre-loxP.... Catalog Add to Search C ) -deficiency the whole-body knockout, beta cell function was directly by...