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Increases in bioactive lipids accompany early metabolic changes associated with β-cell expansion in response to short-term high-fat diet.
Seferovic MD, Beamish CA, Mosser RE, Townsend SE, Pappan K, Poitout V, Aagaard KM, Gannon M
(2018) Am J Physiol Endocrinol Metab 315: E1251-E1263
MeSH Terms: Animals, Blood Glucose, Cell Proliferation, Diabetes Mellitus, Type 2, Diet, High-Fat, Insulin Resistance, Insulin-Secreting Cells, Lipid Metabolism, Lipids, Liver, Male, Mice, Muscle, Skeletal, Obesity
Show Abstract · Added April 15, 2019
Pancreatic β-cell expansion is a highly regulated metabolic adaptation to increased somatic demands, including obesity and pregnancy; adult β cells otherwise rarely proliferate. We previously showed that high-fat diet (HFD) feeding induces mouse β-cell proliferation in less than 1 wk in the absence of insulin resistance. Here we metabolically profiled tissues from a short-term HFD β-cell expansion mouse model to identify pathways and metabolite changes associated with β-cell proliferation. Mice fed HFD vs. chow diet (CD) showed a 14.3% increase in body weight after 7 days; β-cell proliferation increased 1.75-fold without insulin resistance. Plasma from 1-wk HFD-fed mice induced β-cell proliferation ex vivo. The plasma, as well as liver, skeletal muscle, and bone, were assessed by LC and GC mass-spectrometry for global metabolite changes. Of the 1,283 metabolites detected, 159 showed significant changes [false discovery rate (FDR) < 0.1]. The majority of changes were in liver and muscle. Pathway enrichment analysis revealed key metabolic changes in steroid synthesis and lipid metabolism, including free fatty acids and other bioactive lipids. Other important enrichments included changes in the citric acid cycle and 1-carbon metabolism pathways implicated in DNA methylation. Although the minority of changes were observed in bone and plasma (<20), increased p-cresol sulfate was increased >4 fold in plasma (the largest increase in all tissues), and pantothenate (vitamin B) decreased >2-fold. The results suggest that HFD-mediated β-cell expansion is associated with complex, global metabolite changes. The finding could be a significant insight into Type 2 diabetes pathogenesis and potential novel drug targets.
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14 MeSH Terms
HDAC11 suppresses the thermogenic program of adipose tissue via BRD2.
Bagchi RA, Ferguson BS, Stratton MS, Hu T, Cavasin MA, Sun L, Lin YH, Liu D, Londono P, Song K, Pino MF, Sparks LM, Smith SR, Scherer PE, Collins S, Seto E, McKinsey TA
(2018) JCI Insight 3:
MeSH Terms: Adipose Tissue, Brown, Adipose Tissue, White, Adult, Aged, Aged, 80 and over, Animals, Diet, High-Fat, Disease Models, Animal, Energy Metabolism, Epigenesis, Genetic, Fatty Liver, Female, Gene Expression Regulation, Histone Deacetylases, Humans, Insulin Resistance, Male, Mice, Mice, Knockout, Middle Aged, Obesity, Thermogenesis, Transcription Factors
Show Abstract · Added July 22, 2020
Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, improved insulin sensitivity, and reduced hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. These findings define an epigenetic pathway for the regulation of energy homeostasis and suggest the potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.
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Brief exposure to obesogenic diet disrupts brain dopamine networks.
Barry RL, Byun NE, Williams JM, Siuta MA, Tantawy MN, Speed NK, Saunders C, Galli A, Niswender KD, Avison MJ
(2018) PLoS One 13: e0191299
MeSH Terms: Amphetamine, Animals, Brain, Diet, High-Fat, Dopamine, Insulin, Male, Neostriatum, Nerve Net, Obesity, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D2, Signal Transduction, Time Factors
Show Abstract · Added April 11, 2019
OBJECTIVE - We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).
METHODS - We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET).
RESULTS - We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.
CONCLUSION - These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.
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Balanced high fat diet reduces cardiovascular risk in obese women although changes in adipose tissue, lipoproteins, and insulin resistance differ by race.
Niswender KD, Fazio S, Gower BA, Silver HJ
(2018) Metabolism 82: 125-134
MeSH Terms: Adipose Tissue, Adult, African Continental Ancestry Group, Cardiovascular Diseases, Diet, High-Fat, European Continental Ancestry Group, Female, Humans, Insulin Resistance, Lipoproteins, Middle Aged, Obesity, Risk Factors, Young Adult
Show Abstract · Added April 10, 2018
BACKGROUND - We previously reported that consuming a balanced high fat diet (BHFD) wherein total saturated fat was reduced and total unsaturated fat increased by proportionately balancing the type of fat (1/3 saturated, 1/3 monounsaturated, 1/3 polyunsaturated) led to significant improvements in inflammatory burden, blood pressure, and vascular function in obese premenopausal European American (EA) and African American (AA) women.
OBJECTIVE - Here we compared changes in adipose tissue, lipoproteins, insulin resistance, and cardiovascular risk between EA and AA women.
METHODS - Dietary intakes, plasma fatty acids, lipids, apolipoproteins, lipoproteins, HOMA-IR and ASCVD risk was measured in 144 women who consumed BHFD for 16 weeks. Generalized linear modeling was performed while controlling for change in body weight.
RESULTS - EA women had greater reductions in visceral adipose tissue. Only EA women had significant reductions in fasting insulin levels (↓24.8%) and HOMA-IR (↓29%) scores. In EA women, the most significant improvements occurred in VLDL particle size (↑), apolipoprotein B levels (↑), serum TG (↓), number of plasma LDL particles (↓), and serum LDL-cholesterol (↓). In AA women, significant improvements occurred in HDL particle size (↑), number of large HDL particles (↑), and apolipoprotein AI levels (↑). Consequently, both groups had improved ASCVD risk scores (↓5.5%).
CONCLUSIONS - Consuming the balanced high fat diet led to significant reduction in cardiovascular risk factors in both groups. However, the pattern of response to BHFD differed with EA women responding more in components of the apolipoprotein B pathway versus AA women responding more in components of the apolipoprotein AI pathway.
Published by Elsevier Inc.
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14 MeSH Terms
Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
Kropp PA, Dunn JC, Carboneau BA, Stoffers DA, Gannon M
(2018) Am J Physiol Endocrinol Metab 314: E308-E321
MeSH Terms: Adaptation, Physiological, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Diet, High-Fat, Gene Expression Regulation, Developmental, Glucose, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Transgenic, Multipotent Stem Cells, Organogenesis, Trans-Activators
Show Abstract · Added April 15, 2019
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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High-Fat, High-Sugar Diet-Induced Subendothelial Matrix Stiffening is Mitigated by Exercise.
Kohn JC, Azar J, Seta F, Reinhart-King CA
(2018) Cardiovasc Eng Technol 9: 84-93
MeSH Terms: Animals, Aorta, Abdominal, Arterial Pressure, Diet, Healthy, Diet, High-Fat, Dietary Sugars, Disease Models, Animal, Elastic Modulus, Exercise Therapy, Extracellular Matrix, Male, Mice, Inbred C57BL, Microscopy, Atomic Force, Peripheral Arterial Disease, Pulse Wave Analysis, Risk Reduction Behavior, Time Factors, Vascular Stiffness
Show Abstract · Added December 7, 2017
Consumption of a high-fat, high-sugar diet and sedentary lifestyle are correlated with bulk arterial stiffening. While measurements of bulk arterial stiffening are used to assess cardiovascular health clinically, they cannot account for changes to the tissue occurring on the cellular scale. The compliance of the subendothelial matrix in the intima mediates vascular permeability, an initiating step in atherosclerosis. High-fat, high-sugar diet consumption and a sedentary lifestyle both cause micro-scale subendothelial matrix stiffening, but the impact of these factors in concert remains unknown. In this study, mice on a high-fat, high-sugar diet were treated with aerobic exercise or returned to a normal diet. We measured bulk arterial stiffness through pulse wave velocity and subendothelial matrix stiffness ex vivo through atomic force microscopy. Our data indicate that while diet reversal mitigates high-fat, high-sugar diet-induced macro- and micro-scale stiffening, exercise only significantly decreases micro-scale stiffness and not macro-scale stiffness, during the time-scale studied. These data underscore the need for both healthy diet and exercise to maintain vascular health. These data also indicate that exercise may serve as a key lifestyle modification to partially reverse the deleterious impacts of high-fat, high-sugar diet consumption, even while macro-scale stiffness indicators do not change.
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18 MeSH Terms
Microsomal triglyceride transfer protein contributes to lipid droplet maturation in adipocytes.
Swift LL, Love JD, Harris CM, Chang BH, Jerome WG
(2017) PLoS One 12: e0181046
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Body Composition, Carrier Proteins, Diet, High-Fat, Gene Knockdown Techniques, Lipid Droplets, Mice, Mice, Transgenic, Weight Gain
Show Abstract · Added March 3, 2020
Previous studies in our laboratory have established the presence of MTP in both white and brown adipose tissue in mice as well as in 3T3-L1 cells. Additional studies demonstrated an increase in MTP levels as 3T3-L1 cells differentiate into adipocytes concurrent with the movement of MTP from the juxtanuclear region of the cell to the surface of lipid droplets. This suggested a role for MTP in lipid droplet biogenesis and/or maturation. To probe the role of MTP in adipocytes, we used a Cre-Lox approach with aP2-Cre and Adipoq-Cre recombinase transgenic mice to knock down MTP expression in brown and white fat of mice. MTP expression was reduced approximately 55% in white fat and 65-80% in brown fat. Reducing MTP expression in adipose tissue had no effect on weight gain or body composition, whether the mice were fed a regular rodent or high fat diet. In addition, serum lipids and unesterified fatty acid levels were not altered in the knockdown mice. Importantly, decreased MTP expression in adipose tissue was associated with smaller lipid droplets in brown fat and smaller adipocytes in white fat. These results combined with our previous studies showing MTP lipid transfer activity is not necessary for lipid droplet initiation or growth in the early stages of differentiation, suggest that a structural feature of the MTP protein is important in lipid droplet maturation. We conclude that MTP protein plays a critical role in lipid droplet maturation, but does not regulate total body fat accumulation.
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HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning.
Ferrari A, Longo R, Fiorino E, Silva R, Mitro N, Cermenati G, Gilardi F, Desvergne B, Andolfo A, Magagnotti C, Caruso D, Fabiani E, Hiebert SW, Crestani M
(2017) Nat Commun 8: 93
MeSH Terms: Adipocytes, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Line, Diet, High-Fat, Gene Expression Regulation, Gene Silencing, Histone Deacetylases, Lipid Metabolism, Male, Mice, Mice, Knockout
Show Abstract · Added February 7, 2019
White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
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Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1.
Zhang H, Hinkle CC, O'Neill SM, Shi J, Caughey J, Lynch E, Lynch G, Gerelus M, Tsai ASD, Shah R, Ferguson JF, Ahima RS, Reilly MP
(2017) Obesity (Silver Spring) 25: 1410-1420
MeSH Terms: Animals, Body Composition, CX3C Chemokine Receptor 1, Diet, High-Fat, Female, Glucose Intolerance, Inflammation, Insulin, Insulin Resistance, Insulin Secretion, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Receptors, CCR2, Weight Gain
Show Abstract · Added April 2, 2019
OBJECTIVE - The purpose of the study was to explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of obesity induced by a high-fat diet (HFD).
METHODS - C57BL/6J wild-type, Cx3cr1 , Ccr2 , and Cx3cr1 Ccr2 double-knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12 weeks of age.
RESULTS - All groups gained weight at a similar rate and developed a similar degree of adiposity, hyperglycemia, glucose intolerance, and impairment of insulin sensitivity in response to HFD. As expected, the circulating monocyte count was decreased in Ccr2 and Cx3cr1 Ccr2 mice but not in Cx3cr1 mice. Flow cytometric analysis of perigonadal adipose tissue of male, but not female, mice revealed trends to lower CD11c+MGL1- M1-like macrophages and higher CD11c-MGL1+ M2-like macrophages as a percentage of CD45+F4/80+CD11b+ macrophages in Cx3cr1 Ccr2 mice versus wild-type mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes.
CONCLUSIONS - Although CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence the metabolic effects of a 45% HFD-induced obesity in these model conditions.
© 2017 The Obesity Society.
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Hepatic β-arrestin 2 is essential for maintaining euglycemia.
Zhu L, Rossi M, Cui Y, Lee RJ, Sakamoto W, Perry NA, Urs NM, Caron MG, Gurevich VV, Godlewski G, Kunos G, Chen M, Chen W, Wess J
(2017) J Clin Invest 127: 2941-2945
MeSH Terms: Animals, Blood Glucose, COS Cells, Chlorocebus aethiops, Diabetes Mellitus, Type 2, Diet, High-Fat, Gene Deletion, Gene Expression Regulation, Glucagon, Hepatocytes, Homeostasis, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Receptors, Glucagon, Signal Transduction, beta-Arrestin 1, beta-Arrestin 2
Show Abstract · Added March 14, 2018
An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.
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22 MeSH Terms