Effect of Weight Gain on Skeletal Muscle and Adipose Tissue Perfusion
2020; Lippincott Williams & Wilkins; Volume: 40; Issue: 7 Linguagem: Inglês
10.1161/atvbaha.120.314663
ISSN1524-4636
Autores Tópico(s)Adipokines, Inflammation, and Metabolic Diseases
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 40, No. 7Effect of Weight Gain on Skeletal Muscle and Adipose Tissue Perfusion Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEffect of Weight Gain on Skeletal Muscle and Adipose Tissue PerfusionHuman Fat Goes With the Flow Timothy P. Fitzgibbons Timothy P. FitzgibbonsTimothy P. Fitzgibbons Correspondence to: Timothy P. Fitzgibbons, MD, PhD, Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave N, Worcester, MA 01655. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0229-034X Department of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester. Originally published24 Jun 2020https://doi.org/10.1161/ATVBAHA.120.314663Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:1617–1619This article is a commentary on the followingEffects of a Hypercaloric and Hypocaloric Diet on Insulin-Induced Microvascular Recruitment, Glucose Uptake, and Lipolysis in Healthy Lean MenSee accompanying article on page 1695In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Emanuel et al1 present an intriguing paper regarding alterations in adipose tissue (AT) blood flow in response to a short-term hypercaloric diet (HCD). Insulin increases blood flow by dilating conduit arteries and recruiting the microvasculature. This serves to increase concentrations of insulin and nonsoluble macronutrients in the interstitial fluid for target organ uptake. In skeletal muscle (SM), insulin increases blood flow by stimulating capillary endothelial nitric oxide production via the IR (insulin receptor)/PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial nitric oxide synthase) pathway2 (Figure). This effect is blunted in obesity and before the development of insulin resistance.3 In mice fed an HCD, insulin-stimulated Akt phosphorylation is reduced in aortic endothelial cells before SM, liver, or visceral AT.4 Therefore, Emanuel et al1 hypothesized that SM blood flow may be reduced in subjects fed an HCD because of reduced insulin-stimulated NO production. This reduction in blood flow would protect SM from excess glucose and fat and allow it to be redirected to AT for storage.Download figureDownload PowerPointFigure 1. Hypercaloric diet increases adipose tissue blood flow. After a meal in normal conditions (top left), insulin is released and stimulates the IR (insulin receptor) on endothelium in skeletal muscle conductance and resistance blood vessels (BV). This triggers activation of the IRS (IR substrate)/PI3K (phosphoinositide 3-kinase)/Akt pathway and subsequent stimulation of eNOS (endothelial nitric oxide synthase) to produce nitric oxide and cause vasodilation. Insulin also acts centrally to stimulate sympathetic nervous system (SNS) output and dilate blood vessels in adipose tissue (AT) by β1-adrenergic receptor activation. After a short-term hypocaloric diet (top right), perfusion of AT is increased to allow for redirection of glucose and free fatty acids (FFAs) for storage in AT. With weight loss and fasting (bottom left), AT perfusion remains elevated to allow for lipolysis and provision of glucose and FFA to other tissues. If overfeeding continues for a prolonged period of time, obesity and insulin resistance will result (bottom right). With the onset of insulin resistance, insulin is no longer able to trigger increase AT perfusion, and AT may be hypoperfused, leading to the ectopic accumulation of FFA and glucose in peripheral tissues. ANP indicates atrial natriuretic peptide; CNS, central nervous system; ET, endothelin 1; MAPK, mitogen activated protein kinase; MCP1, monocyte chemoattractant protein 1; PAI1, plasminogen activator inhibitor 1; and TNF, tumor necrosis factor.Subjects were men with a mean age of 22 years and mean body mass index of 22. Hyperinsulinemic clamps were done at baseline and SM and AT blood flow was measured at rest and during the clamp via contrast-enhanced ultrasonography. This protocol was repeated after 8 and 30 days of HCD, and after subjects had ingested a hypocaloric diet and returned to baseline weight. The diet intervention caused a mean weight gain of 4 kg of weight gain and a 3% increase in body fat.1 There was a small increase in fasting insulin at 8 weeks, but there was no change in insulin-stimulated glucose uptake or free fatty acids suppression, therefore these subjects were insulin sensitive based on these parameters.The fasting or insulin-stimulated % microvascular recruitment in SM was not altered by diet and was higher in SM than AT at baseline. However, insulin-stimulated AT blood flow increased after 8 and 30 weeks of HCD. The ratio of SM/AT microvascular blood volume did not change in fasting conditions at any point, but the clamp microvascular blood volume tended to decrease with HCD, consistent with an increase in the AT perfusion.This study shows that in healthy human men HCD results in an increase in AT blood flow (Figure). Overall, the effects of short term HCD on AT blood flow were modest. However, the magnitude of the effect may have been underestimated for several reasons. First, there was a small number of subjects and AT blood flow is known to have significant interindividual variability.5 Second, AT in the thigh has lower blood flow than abdominal subcutaneous AT.6 Finally, the concentrations of insulin used during the clamp might be lower than that seen in the postprandial state, although one prior study has shown a 30% increase in microvascular blood volume in females during a hyperinsulinemic clamp.7 In addition to stimulating insulin release and the sympathetic nervous system, feeding also results in release of GLP-1 (glucagon-like peptide-1) and other hormones that have insulin-independent vasodilatory effects.8 These points aside, the effect of HCD on increased insulin-stimulated AT blood flow are novel, consistent, and quite provocative.The regulation of blood flow is a highly complex phenomenon. As the authors suggest, in general, vasodilation of arterioles in AT is not dependent on insulin-stimulated NO production.9,10 Blood flow in AT is predominantly dependent on the sympathetic nervous system and the balance between α1-adrenergic receptor–mediated vasoconstriction and β1-receptor–stimulated vasodilation. Postprandial AT blood flow correlates with the postprandial rise in plasma norepinephrine.5 At baseline, insulin infusion increased cardiac output, and after HCD, the insulin-induced rise in cardiac output was further increased. This augmentation of cardiac output may partly account for the increased AT blood flow seen in HCD subjects.It is interesting to note that AT blood flow remained elevated even after weight loss. Perhaps the HCD primed AT for an increasing need for storage. Alternatively, increased lipolysis during the hypocaloric phase may have necessitated the increased blood flow. It is likely, as the authors suggest, that angiogenesis was stimulated by the HCD and this contributed to increased blood flow.1 Subcutaneous AT is known to have a higher capillary density than visceral AT, and this correlates with insulin sensitivity.11 This hypothesis could have been tested by comparing capillary density in AT samples at the beginning and end of the study.There are numerous molecular differences in endothelial cells throughout the body that are not well understood. In addition to activating eNOS through IR dependent Akt phosphorylation, in nonfenestrated endothelium such as that found in SM, insulin binds to the IR on endothelial cells and transcytoses to the interstitial space in an IRS2 (insulin receptor substrate 2) dependent fashion. At higher concentrations, insulin also stimulates ET-1 production by endothelial cells through the MAPK (mitogen-activated protein kinase) pathway.12 Therefore, it is possible, as the authors suggest, that the failure of microvascular blood volume to increase in SM was due to increased ET (endothelin)-1 production, and not reduced NO production. Preferential activation of the MAPK pathway over the Akt pathway in the endothelial cells has been termed selective insulin resistance.12 If this molecular switch were operative in endothelium of SM and not AT this may have accounted for the change in perfusion observed after HCD. Angiotensin II and atrial natriuretic peptide are additional factors that regulate AT blood flow in humans and these pathways should also be investigated.13,14In summary, this study helps us appreciate the resilience of the human body and the remarkable plasticity of AT. The fact that AT blood flow correlates with insulin sensitivity and can now be measured with a variety of noninvasive techniques will allow for future studies using pharmacological and nonpharmacological approaches (ie, exercise) to increase AT blood flow.DisclosuresNone.FootnotesFor Disclosures, see page 1619.Correspondence to: Timothy P. Fitzgibbons, MD, PhD, Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave N, Worcester, MA 01655. Email timothy.[email protected]orgReferences1. Emanuel AL, Meijer RI, Woerdeman J, van Raalte DH, Diamant M, Kramer MHH, Serlie MJ, Eringa EC, Serné EH. Effects of a hypercaloric and hypocaloric diet on insulin-induced microvascular recruitment, glucose uptake, and lipolysis in healthy lean men.Arterioscler Thromb Vasc Biol. 2020; 40:1695–1704. doi: 10.1161/ATVBAHA.120.314129LinkGoogle Scholar2. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.J Clin Invest. 1994; 94:1172–1179. doi: 10.1172/JCI117433CrossrefMedlineGoogle Scholar3. Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle.Diabetes. 2006; 55:1436–1442. doi: 10.2337/db05-1373CrossrefMedlineGoogle Scholar4. Kim F, Pham M, Maloney E, Rizzo NO, Morton GJ, Wisse BE, Kirk EA, Chait A, Schwartz MW. Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance.Arterioscler Thromb Vasc Biol. 2008; 28:1982–1988. doi: 10.1161/ATVBAHA.108.169722LinkGoogle Scholar5. Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LK, Frayn KN. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity.Diabetes. 2002; 51:2467–2473. doi: 10.2337/diabetes.51.8.2467CrossrefMedlineGoogle Scholar6. Frayn KN, Karpe F. Regulation of human subcutaneous adipose tissue blood flow.Int J Obes (Lond). 2014; 38:1019–1026. doi: 10.1038/ijo.2013.200CrossrefMedlineGoogle Scholar7. Sjøberg KA, Rattigan S, Hiscock N, Richter EA, Kiens B. A new method to study changes in microvascular blood volume in muscle and adipose tissue: real-time imaging in humans and rat.Am J Physiol Heart Circ Physiol. 2011; 301:H450–H458. doi: 10.1152/ajpheart.01174.2010CrossrefMedlineGoogle Scholar8. Wang N, Tan AWK, Jahn LA, Hartline L, Patrie JT, Lin S, Barrett EJ, Aylor KW, Liu Z. Vasodilatory Actions of glucagon-like peptide 1 are preserved in skeletal and cardiac muscle microvasculature but not in conduit artery in obese humans with vascular insulin resistance.Diabetes Care. 2020; 43:634–642. doi: 10.2337/dc19-1465CrossrefMedlineGoogle Scholar9. Ardilouze JL, Fielding BA, Currie JM, Frayn KN, Karpe F. Nitric oxide and beta-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans.Circulation. 2004; 109:47–52. doi: 10.1161/01.CIR.0000105681.70455.73LinkGoogle Scholar10. Manolopoulos KN, Karpe F, Frayn KN. Marked resistance of femoral adipose tissue blood flow and lipolysis to adrenaline in vivo.Diabetologia. 2012; 55:3029–3037. doi: 10.1007/s00125-012-2676-0CrossrefMedlineGoogle Scholar11. Gealekman O, Guseva N, Hartigan C, Apotheker S, Gorgoglione M, Gurav K, Tran KV, Straubhaar J, Nicoloro S, Czech MP, et al. Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity.Circulation. 2011; 123:186–194. doi: 10.1161/CIRCULATIONAHA.110.970145LinkGoogle Scholar12. King GL, Park K, Li Q. Selective insulin resistance and the development of cardiovascular diseases in diabetes: the 2015 Edwin Bierman award lecture.Diabetes. 2016; 65:1462–1471. doi: 10.2337/db16-0152CrossrefMedlineGoogle Scholar13. Birkenfeld AL, Boschmann M, Moro C, Adams F, Heusser K, Franke G, Berlan M, Luft FC, Lafontan M, Jordan J. Lipid mobilization with physiological atrial natriuretic peptide concentrations in humans.J Clin Endocrinol Metab. 2005; 90:3622–3628. doi: 10.1210/jc.2004-1953CrossrefMedlineGoogle Scholar14. Goossens GH, McQuaid SE, Dennis AL, van Baak MA, Blaak EE, Frayn KN, Saris WH, Karpe F. Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans.J Physiol. 2006; 571(pt 2):451–460. doi: 10.1113/jphysiol.2005.101352CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Rosa-Neto J and Silveira L (2020) Endurance Exercise Mitigates Immunometabolic Adipose Tissue Disturbances in Cancer and Obesity, International Journal of Molecular Sciences, 10.3390/ijms21249745, 21:24, (9745) Related articlesEffects of a Hypercaloric and Hypocaloric Diet on Insulin-Induced Microvascular Recruitment, Glucose Uptake, and Lipolysis in Healthy Lean MenAnna L. Emanuel, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:1695-1704 July 2020Vol 40, Issue 7 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.120.314663PMID: 32579478 Originally publishedJune 24, 2020 KeywordsinsulinEditorialsdietinsulin resistanceglucoseobesityPDF download Advertisement SubjectsEchocardiographyMeta AnalysisMortality/SurvivalPulmonary Hypertension
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