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Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice.
McCurdy CE, Schenk S, Holliday MJ, Philp A, Houck JA, Patsouris D, MacLean PS, Majka SM, Klemm DJ, Friedman JE
(2012) Diabetes 61: 2495-505
MeSH Terms: Adipose Tissue, Animals, Class Ia Phosphatidylinositol 3-Kinase, Cytokines, Diet, High-Fat, Insulin, Insulin Resistance, Macrophages, Male, Mice, Mice, Knockout, Obesity, Phosphatidylinositol 3-Kinases
Show Abstract · Added August 4, 2015
Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance; however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α/p55α/p50α) are highly induced in AT from high-fat diet-fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH(2)-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT.
1 Communities
1 Members
0 Resources
13 MeSH Terms
Mitochondrial antioxidative capacity regulates muscle glucose uptake in the conscious mouse: effect of exercise and diet.
Kang L, Lustig ME, Bonner JS, Lee-Young RS, Mayes WH, James FD, Lin CT, Perry CG, Anderson EJ, Neufer PD, Wasserman DH
(2012) J Appl Physiol (1985) 113: 1173-83
MeSH Terms: Action Potentials, Animal Feed, Animals, Antioxidants, Biological Transport, Catalase, Diet, High-Fat, Glucose, Glutathione Disulfide, Hydrogen Peroxide, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Muscle, Skeletal, Nitric Oxide, Physical Conditioning, Animal, Reactive Nitrogen Species, Reactive Oxygen Species, Superoxide Dismutase, Tyrosine
Show Abstract · Added March 18, 2013
The objective of this study was to test the hypothesis that exercise-stimulated muscle glucose uptake (MGU) is augmented by increasing mitochondrial reactive oxygen species (mtROS) scavenging capacity. This hypothesis was tested in genetically altered mice fed chow or a high-fat (HF) diet that accelerates mtROS formation. Mice overexpressing SOD2 (sod2(Tg)), mitochondria-targeted catalase (mcat(Tg)), and combined SOD2 and mCAT (mtAO) were used to increase mtROS scavenging. mtROS was assessed by the H(2)O(2) emitting potential (JH(2)O(2)) in muscle fibers. sod2(Tg) did not decrease JH(2)O(2) in chow-fed mice, but decreased JH(2)O(2) in HF-fed mice. mcat(Tg) and mtAO decreased JH(2)O(2) in both chow- and HF-fed mice. In parallel, the ratio of reduced to oxidized glutathione (GSH/GSSG) was unaltered in sod2(Tg) in chow-fed mice, but was increased in HF-fed sod2(Tg) and both chow- and HF-fed mcat(Tg) and mtAO. Nitrotyrosine, a marker of NO-dependent, reactive nitrogen species (RNS)-induced nitrative stress, was decreased in both chow- and HF-fed sod2(Tg), mcat(Tg), and mtAO mice. This effect was not changed with exercise. Kg, an index of MGU was assessed using 2-[(14)C]-deoxyglucose during exercise. In chow-fed mice, sod2(Tg), mcat(Tg), and mtAO increased exercise Kg compared with wild types. Exercise Kg was also augmented in HF-fed sod2(Tg) and mcat(Tg) mice but unchanged in HF-fed mtAO mice. In conclusion, mtROS scavenging is a key regulator of exercise-mediated MGU and this regulation depends on nutritional state.
2 Communities
3 Members
0 Resources
21 MeSH Terms
Effects of voluntary running on oxygen consumption, RQ, and energy expenditure during primary prevention of diet-induced obesity in C57BL/6N mice.
Brown JD, Naples SP, Booth FW
(2012) J Appl Physiol (1985) 113: 473-8
MeSH Terms: Animals, Calorimetry, Indirect, Diet, High-Fat, Energy Metabolism, Female, Mice, Mice, Inbred C57BL, Obesity, Oxygen Consumption, Respiration, Running
Show Abstract · Added October 23, 2017
Diet-induced obesity (DIO) in C57BL/6 mice is the standard model for studying obesity in mice. The few reports of DIO utilizing voluntary running provide contradictory results with respect to prevention of obesity. However, total energy expenditures associated with voluntary running during DIO are unknown. We hypothesized that voluntary running would increase the amount of total energy expended during DIO. Female C57BL/6N mice were randomly assigned to one of three experimental groups [high-fat diet with voluntary running (HFRun); high-fat diet without running (HFSed); and low-fat diet without running (LFSed)] for a 10-wk period. We confirmed production of obesity in HFSed, and more importantly demonstrated primary prevention of obesity by voluntary running in a group of cohorts (HFRun). Indirect calorimetry was performed to determine oxygen consumption (Vo(2)) and respiratory quotient (RQ). The following novel mechanisms were identified in female C57BL/6N mice: 1) HFRun showed ∼2 times greater total energy expenditures during a day compared with HFSed and LFSed; 2) HFRun had increased Vo(2) compared with HFSed and LFSed, lower RQ in the light period than HFSed, and lower RQ in both light and dark periods than LFSed; and 3) in the HFRun group, the magnitude of change in Vo(2) and RQ differed in dark and light periods during voluntary running. Our data combined with existing literature point to a potential threshold of physical activity that would prevent DIO in this mouse model. These data give a mechanistic explanation to resolve contradictory reports on whether voluntary running can prevent obesity in the DIO mouse model. In conclusion, voluntary running rescues high-fat fed, female C57BL/6N mice from obesity in DIO by doubling energy expenditure during the dark period and significantly increasing energy expenditure during the light cycle.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Unconventional microarray design reveals the response to obesity is largely tissue specific: analysis of common and divergent responses to diet-induced obesity in insulin-sensitive tissues.
Lee RK, Hittel DS, Nyamandi VZ, Kang L, Soh J, Sensen CW, Shearer J
(2012) Appl Physiol Nutr Metab 37: 257-68
MeSH Terms: Adipose Tissue, Adipose Tissue, White, Animals, DNA, Complementary, Diet, High-Fat, Dietary Fats, Gene Expression Profiling, Heart, Inflammation, Insulin Resistance, Liver, Male, Mice, Mice, Inbred C57BL, Multigene Family, Muscle, Skeletal, Obesity, Oligonucleotide Array Sequence Analysis, Signal Transduction
Show Abstract · Added March 5, 2013
Obesity is a chronic condition involving the excessive accumulation of adipose tissue that adversely affects all systems in the body. The aim of the present study was to employ an unbiased, genome-wide assessment of transcript abundance in order to identify common gene expression pathways within insulin-sensitive tissues in response to dietary-induced diabetes. Following 20 weeks of chow or high-fat feeding (60% kcal), age-matched mice underwent a euglycemic-hyperinsulinemic clamp to assess insulin sensitivity. High-fat-fed animals were obese and highly insulin resistant, disposing of ∼75% less glucose compared with their chow-fed counterparts. Tissues were collected, and gene expression was examined by microarray in 4 tissues known to exhibit obesity-related metabolic disturbances: white adipose tissue, skeletal muscle, liver, and heart. A total of 463 genes were differentially expressed between diets. Analysis of individual tissues showed skeletal muscle to exhibit the largest number of differentially expressed genes (191) in response to high-fat feeding, followed by adipose tissue (169), liver (115), and heart (65). Analyses revealed that the response of individual genes to obesity is distinct and largely tissue specific, with less than 10% of transcripts being shared among tissues. Although transcripts are largely tissue specific, a systems approach shows numerous commonly activated pathways, including those involved in signal transduction, inflammation, oxidative stress, substrate transport, and metabolism. This suggests a coordinated attempt by tissues to limit metabolic perturbations occurring in early-stage obesity. Many identified genes were associated with a variety of disorders, thereby serving as potential links between obesity and its related health risks.
0 Communities
1 Members
0 Resources
19 MeSH Terms
CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action.
Lord CC, Betters JL, Ivanova PT, Milne SB, Myers DS, Madenspacher J, Thomas G, Chung S, Liu M, Davis MA, Lee RG, Crooke RM, Graham MJ, Parks JS, Brasaemle DL, Fessler MB, Brown HA, Brown JM
(2012) Diabetes 61: 355-63
MeSH Terms: 1-Acylglycerol-3-Phosphate O-Acyltransferase, Acyltransferases, Animals, Diet, High-Fat, Endotoxins, Inflammation, Insulin Resistance, Lipolysis, Liver, Male, Mice, Mice, Inbred C57BL, Signal Transduction, Triglycerides, Tumor Necrosis Factor-alpha
Show Abstract · Added March 21, 2013
Mutations of comparative gene identification 58 (CGI-58) in humans cause Chanarin-Dorfman syndrome, a rare autosomal recessive disease in which excess triacylglycerol (TAG) accumulates in multiple tissues. CGI-58 recently has been ascribed two distinct biochemical activities, including coactivation of adipose triglyceride lipase and acylation of lysophosphatidic acid (LPA). It is noteworthy that both the substrate (LPA) and the product (phosphatidic acid) of the LPA acyltransferase reaction are well-known signaling lipids. Therefore, we hypothesized that CGI-58 is involved in generating lipid mediators that regulate TAG metabolism and insulin sensitivity. Here, we show that CGI-58 is required for the generation of signaling lipids in response to inflammatory stimuli and that lipid second messengers generated by CGI-58 play a critical role in maintaining the balance between inflammation and insulin action. Furthermore, we show that CGI-58 is necessary for maximal TH1 cytokine signaling in the liver. This novel role for CGI-58 in cytokine signaling may explain why diminished CGI-58 expression causes severe hepatic lipid accumulation yet paradoxically improves hepatic insulin action. Collectively, these findings establish that CGI-58 provides a novel source of signaling lipids. These findings contribute insight into the basic mechanisms linking TH1 cytokine signaling to nutrient metabolism.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones.
Martinez MN, Emfinger CH, Overton M, Hill S, Ramaswamy TS, Cappel DA, Wu K, Fazio S, McDonald WH, Hachey DL, Tabb DL, Stafford JM
(2012) J Lipid Res 53: 379-89
MeSH Terms: Animals, Apolipoprotein C-II, Apolipoproteins A, Blotting, Western, Cholesterol, Cholesterol Ester Transfer Proteins, Chromatography, High Pressure Liquid, Computational Biology, Diet, High-Fat, Female, Hyperinsulinism, Insulin, Lipoproteins, HDL, Lipoproteins, VLDL, Mice, Mice, Transgenic, Obesity, Ovariectomy, Triglycerides, Weight Gain
Show Abstract · Added December 10, 2013
Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function.
1 Communities
5 Members
0 Resources
20 MeSH Terms
Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis.
Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP
(2012) Biochim Biophys Acta 1822: 185-95
MeSH Terms: AMP-Activated Protein Kinases, Animals, Berberine, Cell Line, Diet, High-Fat, Glucose, Hormones, Hyperglycemia, Insulin Resistance, Male, Mice, Mitochondria, Mitochondria, Muscle, Muscle, Skeletal, Myoblasts, NAD, Obesity, Organelle Biogenesis, Phosphorylation, Rats, Rats, Sprague-Dawley, Sirtuin 1
Show Abstract · Added April 25, 2013
Berberine (BBR) has recently been shown to improve insulin sensitivity in rodent models of insulin resistance. Although this effect was explained partly through an observed activation of AMP-activated protein kinase (AMPK), the upstream and downstream mediators of this phenotype were not explored. Here, we show that BBR supplementation reverts mitochondrial dysfunction induced by High Fat Diet (HFD) and hyperglycemia in skeletal muscle, in part due to an increase in mitochondrial biogenesis. Furthermore, we observe that the prevention of mitochondrial dysfunction by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells in which SIRT1 has been knocked-down. Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance.
Copyright © 2011 Elsevier B.V. All rights reserved.
0 Communities
0 Members
1 Resources
22 MeSH Terms
Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.
Speed N, Saunders C, Davis AR, Owens WA, Matthies HJ, Saadat S, Kennedy JP, Vaughan RA, Neve RL, Lindsley CW, Russo SJ, Daws LC, Niswender KD, Galli A
(2011) PLoS One 6: e25169
MeSH Terms: Animals, Biological Transport, Biotinylation, Brain, Cell Membrane, Corpus Striatum, Diet, High-Fat, Dopamine, Homeostasis, Insulin, Locomotion, Male, Obesity, Proto-Oncogene Proteins c-akt, Rats, Rats, Sprague-Dawley, Signal Transduction, Substantia Nigra
Show Abstract · Added September 17, 2013
BACKGROUND - The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.
METHODOLOGY/PRINCIPAL FINDINGS - We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.
CONCLUSIONS/SIGNIFICANCE - Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food lifestyle" creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.
0 Communities
3 Members
0 Resources
18 MeSH Terms