scholarly journals Essential Role of IGFIR in the Onset of Male Brown Fat Thermogenic Function: Regulation of Glucose Homeostasis by Differential Organ-Specific Insulin Sensitivity

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1495-1511 ◽  
Author(s):  
Vanesa Viana-Huete ◽  
Carlos Guillén ◽  
Ana García-Aguilar ◽  
Gema García ◽  
Silvia Fernández ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
High Plasma ◽  
Brown Fat ◽  
Severe Insulin Resistance ◽  
Brown Adipose ◽  
Total Fat

Abstract Brown fat is a thermogenic tissue that generates heat to maintain body temperature in cold environments and dissipate excess energy in response to overfeeding. We have addressed the role of the IGFIR in the brown fat development and function. Mice lacking IGFIR exhibited normal brown adipose tissue/body weight in knockout (KO) vs control mice. However, lack of IGFIR decreased uncoupling protein 1 expression in interscapular brown fat and beige cells in inguinal fat. More importantly, the lack of IGFIR resulted in an impaired cold acclimation. No differences in the total fat volume were found in the KO vs control mice. Epididymal fat showed larger adipocytes but with a lower number of adipocytes in KO vs control mice at age 12 months. In addition, KO mice showed a sustained moderate hyperinsulinemia and hypertriglyceridemia upon time and hepatic insulin insensitivity associated with lipid accumulation, with the outcome of a global insulin resistance. In addition, we found that the expression of uncoupling protein 3 in the skeletal muscle was decreased and its expression was increased in the heart in parallel with the expression of beta-2 adrenergic receptors. Upon nonobesogenic high-fat diet, we found a severe insulin resistance in the liver and in the skeletal muscle, but unchanged insulin sensitivity in the heart. In conclusion, our data suggest that IGFIR it is not an essential growth factor in the brown fat development in the presence of the IR and very high plasma levels of IGF-I, but it is indispensable for full brown fat functionality.

Dissociation of obesity and insulin resistance in transgenic mice with skeletal muscle expression of uncoupling protein 1

2008 ◽  
Vol 32 (3) ◽  
pp. 352-359 ◽  
Author(s):  
Yvonne Katterle ◽  
Susanne Keipert ◽  
Jana Hof ◽  
Susanne Klaus
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Wild Type ◽  
Uncoupling Protein 1 ◽  
Mitochondrial Uncoupling ◽  
High Fat Diets ◽  
Fat Diets ◽  
White Fat

We evaluated the effect of skeletal muscle mitochondrial uncoupling on energy and glucose metabolism under different diets. For 3 mo, transgenic HSA-mUCP1 mice with ectopic expression of uncoupling protein 1 in skeletal muscle and wild-type littermates were fed semisynthetic diets with varying macronutrient ratios (energy % carbohydrate-protein-fat): HCLF (41:42:17), HCHF (41:16:43); LCHF (11:45:44). Body composition, energy metabolism, and insulin resistance were assessed by NMR, indirect calorimetry, and insulin tolerance test, respectively. Gene expression in different organs was determined by real-time PCR. In wild type, both high-fat diets led to an increase in body weight and fat. HSA-mUCP1 mice considerably increased body fat on HCHF but stayed lean on the other diets. Irrespective of differences in body fat content, HSA-mUCP1 mice showed higher insulin sensitivity and decreased plasma insulin and liver triglycerides. Respiratory quotient and gene expression indicated overall increased carbohydrate oxidation of HSA-mUCP1 but a preferential channeling of fatty acids into muscle rather than liver with high-fat diets. Evidence for increased lipogenesis in white fat of HSA-mUCP1 mice suggests increased energy dissipating substrate cycling. Retinol binding protein 4 expression in white fat was increased in HSA-mUCP1 mice despite increased insulin sensitivity, excluding a causal role in the development of insulin resistance. We conclude that skeletal muscle mitochondrial uncoupling does not protect from the development of obesity in all circumstances. Rather it can lead to a “healthy” obese phenotype by preserving insulin sensitivity and a high metabolic flexibility, thus protecting from the development of obesity associated disturbances of glucose homeostasis.

scholarly journals Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

2009 ◽  
Vol 201 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Camilla Alexanderson ◽  
Elias Eriksson ◽  
Elisabet Stener-Victorin ◽  
Malin Lönn ◽  
Agneta Holmäng
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Female Rats ◽  
Whole Body ◽  
Low Grade ◽  
Expression Of Genes ◽  
Genes Encoding

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

scholarly journals Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

2007 ◽  
Vol 194 (1) ◽  
pp. 131-141 ◽  
Author(s):  
Fernando Escrivá ◽  
M Lucía Gavete ◽  
Yasmín Fermín ◽  
Coralia Pérez ◽  
Nilda Gallardo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Calorie Restriction ◽  
Food Restriction ◽  
Glucose Utilization ◽  
Oral Glucose ◽  
Old Rats ◽  
Total Fat ◽  
Total Body

Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyper-insulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8- and 24-month-old rats after 3 months of calorie restriction. Body composition and adipocyte-derived cytokines such as leptin, resistin, and adiponectin were analyzed. Overall insulin sensitivity decreases with ageing. Calorie restriction improves global insulin sensitivity in 8- but not in 24-month-old rats. Insulin-stimulated glucose utilization in adipose tissues decreases in 8 months, while in oxidative muscles it reaches significance only in older rats. Calorie restriction restores adipose tissue insulin sensitivity only in 8-month-old rats and no changes are observed in muscles of 24-month-old rats. Resistin and leptin increase with ageing. Food restriction lowers resistin and increases adiponectin in 8-month-old rats and decreases leptin in both ages. Visceral and total fat increase with ageing and decrease after calorie restriction. We conclude that accretion of visceral fat plays a key role in the development of insulin resistance after sexual maturity, which is reversible by calorie restriction. With aging, accumulation of retroperitoneal and total body fat leads to impaired muscle glucose uptake and to a state of insulin resistance that is difficult to reverse.

scholarly journals Chronic Blockade of Nitric Oxide Synthesis Reduces Adiposity and Improves Insulin Resistance in High Fat-Induced Obese Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4548-4556 ◽  
Author(s):  
Kyoichiro Tsuchiya ◽  
Haruna Sakai ◽  
Noriko Suzuki ◽  
Fumiko Iwashima ◽  
Takanobu Yoshimoto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Uncoupling Protein ◽  
Serine Phosphorylation ◽  
Mrna Levels ◽  
Obese Mice ◽  
High Fat ◽  
Brown Adipose

Genetic deletion of inducible nitric oxide synthase (NOS) in mice has been shown to improve high-fat diet (HFD)-induced insulin resistance. However, a pathophysiological role of endogenous nitric oxide (NO) in obesity-related insulin resistance remains controversial. To address this issue, we examined the metabolic phenotypes in HFD-induced obese mice with chronic blockade of NO synthesis by a NOS inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). Six-week-old male C57BL/6j mice were provided free access to either a standard diet (SD) or a HFD and tap water with or without L-NAME (100 mg/kg·d) for 12 wk. L-NAME treatment significantly attenuated body weight gain of mice fed either SD or HFD without affecting calorie intake. L-NAME treatment in HFD-fed mice improved glucose tolerance and insulin sensitivity. HFD feeding induced inducible NOS mRNA expression, but not the other two NOS isoforms, in white adipose tissue (WAT) and skeletal muscle. L-NAME treatment up-regulated uncoupling protein-1 in brown adipose tissue of HFD-fed mice but down-regulated monocyte chemoattractant protein-1 and CD68 mRNAs levels in WAT. HFD feeding up-regulated leptin mRNA levels but conversely down-regulated adiponectin mRNA levels in WAT, but these effects were unaffected by L-NAME treatment. Moreover, L-NAME treatment also increased peroxisome proliferator-uncoupling protein-3 mRNA levels in skeletal muscles of HFD-fed mice. Increased urinary excretion of norepinephrine after HFD feeding was augmented in L-NAME-treated mice. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and serine phosphorylation of Akt/Akt2 in soleus muscle was markedly impaired in HFD-fed mice but reversed by L-NAME treatment. In conclusion, chronic NOS blockade by L-NAME in mice ameliorates HFD-induced adiposity and glucose intolerance, accompanied by reduced adipose inflammation and improved insulin signaling in skeletal muscle, suggesting that endogenous NO plays a modulatory role in the development of obesity-related insulin resistance.

scholarly journals The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

2016 ◽  
Vol 40 (5) ◽  
pp. 1207-1220 ◽  
Author(s):  
Agnieszka U. Blachnio-Zabielska ◽  
Marta Chacinska ◽  
Mikkel H. Vendelbo ◽  
Piotr Zabielski
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
De Novo ◽  
Synthesis Rate ◽  
Standard Diet ◽  
Bioactive Lipids ◽  
Skeletal Muscle Insulin Resistance ◽  
Lipid Species

Background/Aims: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. Methods: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U13C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Results: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr-treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl-Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. Conclusion: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats.

scholarly journals Intramuscular Injection of miR-1 Reduces Insulin Resistance in Obese Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Alice C. Rodrigues ◽  
Alexandre R. Spagnol ◽  
Flávia de Toledo Frias ◽  
Mariana de Mendonça ◽  
Hygor N. Araújo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Insulin Sensitivity ◽  
Mitochondrial Respiration ◽  
High Fat Diet ◽  
C2c12 Cells ◽  
High Fat ◽  
Spare Capacity

The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.

scholarly journals Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity

2016 ◽  
Vol 310 (3) ◽  
pp. E190-E199 ◽  
Author(s):  
Young-Min Park ◽  
R. Scott Rector ◽  
John P. Thyfault ◽  
Terese M. Zidon ◽  
Jaume Padilla ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Capacity ◽  
Tissue Specific ◽  
Subcutaneous White Adipose Tissue ◽  
Brown Adipose ◽  
Glucose Clearance

High-capacity running (HCR) rats are protected against the early (i.e., ∼11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats ( n = 40; aged ∼22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-3H]glucose was used to determine glucose clearance, whereas 2-[14C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR ( P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼40% greater gastrocnemius glucose uptake compared with LCR ( P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR ( P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.

scholarly journals Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

2011 ◽  
Vol 441 (1) ◽  
pp. 285-296 ◽  
Author(s):  
Paul J. Meakin ◽  
Alex J. Harper ◽  
D. Lee Hamilton ◽  
Jennifer Gallagher ◽  
Alison D. McNeilly ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Essential Feature ◽  
Critical Role ◽  
Glucose Disposal ◽  
Glucose Homoeostasis ◽  
Diet Induced Obesity ◽  
Brown Adipose

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes.

scholarly journals Brown fat is essential for cold-induced thermogenesis but not for obesity resistance in aP2-Ucp mice

1998 ◽  
Vol 274 (3) ◽  
pp. E527-E533 ◽  
Author(s):  
Bohumír Stefl ◽  
Alena Janovská ◽  
Zdenek Hodný ◽  
Martin Rossmeisl ◽  
Milada Horáková ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Transgenic Animals ◽  
Brown Fat ◽  
Mitochondrial Uncoupling ◽  
Brown Adipose ◽  
Total Energy Balance

The role of brown adipose tissue in total energy balance and cold-induced thermogenesis was studied. Mice expressing mitochondrial uncoupling protein 1 (UCP-1) from the fat-specific aP2 gene promoter (heterozygous and homozygous aP2 -Ucp transgenic mice) and their nontransgenic C57BL6/J littermates were used. The transgenic animals are resistant to obesity induced by a high-fat diet, presumably due to ectopic synthesis of UCP-1 in white fat. These animals exhibited atrophy of brown adipose tissue, as indicated by smaller size of brown fat and reduction of its total UCP-1 and DNA contents. Norepinephrine-induced respiration (measured in pentobarbital sodium-anesthetized animals) was decreased proportionally to the dosage of the transgene, and the homozygous (but not heterozygous) transgenic mice exhibited a reduction in their capacity to maintain body temperature in the cold. Our results indicate that the role of brown fat in cold-induced thermogenesis cannot be substituted by increased energy expenditure in other tissues.

scholarly journals Olive Leaf Extract Supplementation to Old Wistar Rats Attenuates Aging-Induced Sarcopenia and Increases Insulin Sensitivity in Adipose Tissue and Skeletal Muscle

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 737
Author(s):  
Daniel González-Hedström ◽  
Teresa Priego ◽  
Sara Amor ◽  
María de la Fuente-Fernández ◽  
Ana Isabel Martín ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Brown Adipose Tissue ◽  
Wistar Rats ◽  
Leaf Extract ◽  
Olive Leaf ◽  
Olive Leaf Extract ◽  
Brown Adipose

Aging is associated with increased visceral adiposity and a decrease in the amount of brown adipose tissue and muscle mass, known as sarcopenia, which results in the development of metabolic alterations such as insulin resistance. In this study, we aimed to analyze whether 3-week supplementation with a phenolic-rich olive leaf extract (OLE) to 24 months-old male Wistar rats orally (100 mg/kg) attenuated the aging-induced alterations in body composition and insulin resistance. OLE treatment increased brown adipose tissue and attenuated the aging-induced decrease in protein content and gastrocnemius weight. Treatment with OLE prevented the aging-induced increase in the expression of PPAR-γ in visceral and brown adipose tissues, while it significantly increased the expression of PPAR-α in the gastrocnemius of old rats and reduced various markers related to sarcopenia such as myostatin, HDAC-4, myogenin and MyoD. OLE supplementation increased insulin sensitivity in explants of gastrocnemius and epididymal visceral adipose tissue from aged rats through a greater activation of the PI3K/Akt pathway, probably through the attenuation of inflammation in both tissues. In conclusion, supplementation with OLE prevents the loss of muscle mass associated with aging and exerts anti-inflammatory and insulin-sensitizing effects on adipose tissue and skeletal muscle.

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