المؤلفون: Emily A. Day, Logan K. Townsend, Sonia Rehal, Battsetseg Batchuluun, Dongdong Wang, Marisa R. Morrow, Rachel Lu, Lucie Lundenberg, Jessie H. Lu, Eric M. Desjardins, Tyler K.T. Smith, Amogelang R. Raphenya, Andrew G. McArthur, Morgan D. Fullerton, Gregory R. Steinberg

المصدر: iScience, Vol 26, Iss 11, Pp 108269- (2023)

مصطلحات موضوعية: Immunology, Science

الوصف: Summary: Atherosclerotic cardiovascular disease is characterized by both chronic low-grade inflammation and dyslipidemia. The AMP-activated protein kinase (AMPK) inhibits cholesterol synthesis and dampens inflammation but whether pharmacological activation reduces atherosclerosis is equivocal. In the current study, we found that the orally bioavailable and highly selective activator of AMPKβ1 complexes, PF-06409577, reduced atherosclerosis in two mouse models in a myeloid-derived AMPKβ1 dependent manner, suggesting a critical role for macrophages. In bone marrow-derived macrophages (BMDMs), PF-06409577 dose dependently activated AMPK as indicated by increased phosphorylation of downstream substrates ULK1 and acetyl-CoA carboxylase (ACC), which are important for autophagy and fatty acid oxidation/de novo lipogenesis, respectively. Treatment of BMDMs with PF-06409577 suppressed fatty acid and cholesterol synthesis and transcripts related to the inflammatory response while increasing transcripts important for autophagy through AMPKβ1. These data indicate that pharmacologically targeting macrophage AMPKβ1 may be a promising strategy for reducing atherosclerosis.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589004223023465Test; https://doaj.org/toc/2589-0042Test

الوصول الحر: https://doaj.org/article/3e71dfd38cb24b0fa08de9d413beeee1Test

المؤلفون: Amy C. Burke, Brian G. Sutherland, Dawn E. Telford, Marisa R. Morrow, Cynthia G. Sawyez, Jane Y. Edwards, Maria Drangova, Murray W. Huff

المصدر: Journal of Lipid Research, Vol 59, Iss 9, Pp 1714-1728 (2018)

مصطلحات موضوعية: steatohepatitis, beta oxidation, insulin resistance, hypolipidemic drugs, low density lipoprotein receptor-deficient mice, Biochemistry, QD415-436

الوصف: Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in Ldlr−/− mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in Ldlr−/− mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520335409Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/761ce2d5872b400187ff5a277fcec253Test

المؤلفون: Evangelia E. Tsakiridis, Marisa R. Morrow, Eric M. Desjardins, Dongdong Wang, Andrea Llanos, Bo Wang, Michael G. Wade, Katherine M. Morrison, Alison C. Holloway, Gregory R. Steinberg

المصدر: Food and Chemical Toxicology. 176:113763

مصطلحات موضوعية: General Medicine, Toxicology, Food Science

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::ebd54ee6d485414916b86976ea486582Test
https://doi.org/10.1016/j.fct.2023.113763Test

المؤلفون: Marisa R. Morrow, Battsetseg Batchuluun, Jianhan Wu, Elham Ahmadi, Julie M. Leroux, Pedrum Mohammadi-Shemirani, Eric M. Desjardins, Zhichao Wang, Evangelia E. Tsakiridis, Declan C.T. Lavoie, Amir Reihani, Brennan K. Smith, Jacek M. Kwiecien, James S.V. Lally, Tracy L. Nero, Michael W. Parker, Kjetil Ask, John W. Scott, Lei Jiang, Guillaume Paré, Stephen L. Pinkosky, Gregory R. Steinberg

مصطلحات موضوعية: gluconeogenesis, diabetes, Physiology, cardiovascular disease, hypertriglyceridemia, insulin resistance, NASH, steatosis, Cell Biology, non-alcoholic steatohepatitis, Molecular Biology, lipogenesis, fatty acid oxidation

الوصف: Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d88d7d1921c37707087035fd09835afTest
https://acuresearchbank.acu.edu.au/item/8yw2q/inhibition-of-atp-citrate-lyase-improves-nash-liver-fibrosis-and-dyslipidemiaTest

المؤلفون: Gregory R. Steinberg, Natalia McInnes, Brennan K. Smith, Rachel Lu, Sibylle Hess, Emily A. Day, Pedrum Mohammadi-Shemirani, Andrew G. McArthur, Marisa R Morrow, Robert M Gutgesell, Amogelang R. Raphenya, Mostafa Kabiri, Guillaume Paré, Rebecca J. Ford, Hertzel C. Gerstein

المصدر: Nature Metabolism. 1:1202-1208

مصطلحات موضوعية: medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, media_common.quotation_subject, 030209 endocrinology & metabolism, Type 2 diabetes, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Oral administration, Physiology (medical), Internal medicine, Diabetes mellitus, Internal Medicine, medicine, 030304 developmental biology, media_common, 2. Zero hunger, 0303 health sciences, business.industry, Insulin, nutritional and metabolic diseases, Appetite, Cell Biology, medicine.disease, 3. Good health, Metformin, Endocrinology, GDF15, medicine.symptom, business, medicine.drug

الوصف: Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::72bbe64446bff12e74ccec37fecb4bddTest
https://doi.org/10.1038/s42255-019-0146-4Test

المؤلفون: Marisa R. Morrow, Brian G. Sutherland, Jane Y. Edwards, Dawn E. Telford, Amy C. Burke, Maria Drangova, Cynthia G. Sawyez, Murray W. Huff

المصدر: Journal of Lipid Research, Vol 59, Iss 9, Pp 1714-1728 (2018)
Medical Biophysics Publications
Bone and Joint Institute

مصطلحات موضوعية: 0301 basic medicine, Male, Citrus, low density lipoprotein receptor-deficient mice, White adipose tissue, 030204 cardiovascular system & hematology, Biochemistry, Nobiletin, Monocytes, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, beta oxidation, insulin resistance, Hyperlipidemia, hypolipidemic drugs, Medicine and Health Sciences, Research Articles, 2. Zero hunger, Metabolic Syndrome, food and beverages, 3. Good health, Cholesterol, Adipose Tissue, medicine.medical_specialty, steatohepatitis, Hyperlipidemias, QD415-436, Diet, High-Fat, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Animals, Obesity, Flavonoids, business.industry, Macrophages, Body Weight, Cell Biology, medicine.disease, Atherosclerosis, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Receptors, LDL, Steatosis, Steatohepatitis, Metabolic syndrome, business, Energy Metabolism

الوصف: Copyright © 2018 Burke et al. Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in Ldlr/ mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in Ldlr/ mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f221864abbec4ab66bd0eb13e40524ddTest
http://www.sciencedirect.com/science/article/pii/S0022227520335409Test

المؤلفون: Bo Wang, Katherine M. Morrison, Andrea Llanos, Alison C. Holloway, Marisa R Morrow, Evangelia E. Tsakiridis, Gregory R. Steinberg

المصدر: Journal of the Endocrine Society

مصطلحات موضوعية: medicine.medical_specialty, Pyrethroid, Adipose Tissue, Appetite, and Obesity, business.industry, Endocrinology, Diabetes and Metabolism, Pesticide, medicine.disease, C57bl 6j, High fat diet induced obesity, chemistry.chemical_compound, Insulin resistance, Deltamethrin, Endocrinology, chemistry, Internal medicine, parasitic diseases, Medicine, business, Novel Mechanisms Controlling Adipose Tissue Physiology and Energy Balance, AcademicSubjects/MED00250

الوصف: Deltamethrin is a commonly used pesticide for the control of mosquito populations. Despite widespread use, the effects of deltamethrin on adiposity and glucose homeostasis have been equivocal with some studies showing increased, decreased and no effect on adiposity and glycemic control. However, no study to date has investigated the effect of deltamethrin in mice housed at thermoneutral temperatures, which is important for modelling metabolic diseases in rodents due to reduced thermal stress and constitutive activation of brown adipose tissue. In the current study we demonstrate for the first time that deltamethrin reduces uncoupling protein-1 expression in brown adipocytes cultured in vitro at concentrations as low as 1pm. Meanwhile, in-vivo deltamethrin does not appear to alter glycemic control or promote adiposity at exposures equivalent to 0.01, 0.1 or 1.0 mg/kg/day. Together, our study demonstrates environmentally relevant exposure to deltamethrin does not exacerbate diet induced obesity or insulin resistance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96d3758ec2b401ddfa657dfaa44992feTest
http://europepmc.org/articles/PMC8089330Test

المؤلفون: Hertzel C. Gerstein, Gregory R. Steinberg, Mostafa Kabiri, Andrew G. McArthur, Marisa R Morrow, Guillaume Paré, Pedrum Mohammadi-Shemirani, Brennan K. Smith, Amogelang R. Raphenya, Rachel Lu, Sibylle Hess, Emily A. Day, Rebecca J. Ford, Robert M Gutgesell, Natalia McInnes

المصدر: Yearbook of Paediatric Endocrinology.

مصطلحات موضوعية: 2. Zero hunger, medicine.medical_specialty, endocrine system diseases, business.industry, media_common.quotation_subject, ATF4, nutritional and metabolic diseases, Appetite, Type 2 diabetes, medicine.disease, 3. Good health, Metformin, Endocrinology, Weight loss, Oral administration, Internal medicine, medicine, Endocrine system, GDF15, medicine.symptom, business, media_common, medicine.drug

الوصف: Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::16f6d5deffbdaec755bde3c5f0cdd50aTest
https://doi.org/10.1530/ey.17.11.13Test

المؤلفون: Emily A, Day, Rebecca J, Ford, Brennan K, Smith, Pedrum, Mohammadi-Shemirani, Marisa R, Morrow, Robert M, Gutgesell, Rachel, Lu, Amogelang R, Raphenya, Mostafa, Kabiri, Andrew G, McArthur, Natalia, McInnes, Sibylle, Hess, Guillaume, Paré, Hertzel C, Gerstein, Gregory R, Steinberg

المصدر: Nature metabolism. 1(12)

مصطلحات موضوعية: Male, Growth Differentiation Factor 15, Body Weight, Primary Cell Culture, Diet, High-Fat, Metformin, Up-Regulation, Eating, Mice, Diabetes Mellitus, Type 2, Appetite Depressants, Glucose Intolerance, Weight Loss, Hepatocytes, Animals, Humans, Hypoglycemic Agents, Insulin

الوصف: Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::4546008484276758a7cc3d298d78fc9fTest
https://pubmed.ncbi.nlm.nih.gov/32694673Test

المؤلفون: Dawn E. Telford, Cynthia G. Sawyez, Amy C. Burke, Jane Y. Edwards, Brian G. Sutherland, Marisa R. Morrow, Murray W. Huff

المصدر: Atherosclerosis Supplements. 32:23

مصطلحات موضوعية: Naringenin, Food intake, chemistry.chemical_compound, Energy expenditure, Chemistry, LDL receptor, Internal Medicine, General Medicine, Food science, Cardiology and Cardiovascular Medicine, Chow diet, Beta oxidation

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::92f51e3e85b645e81d37ad85f1fb9197Test
https://doi.org/10.1016/j.atherosclerosissup.2018.04.068Test