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Obesity and the Dysregulation of Fatty Acid Metabolism: Implications for Healthy Aging
Introduction. The population of the world is aging. In 2010, an estimated 524 million people were aged 65 years or older presenting eight percent of the global population. By 2050, this number is expected to nearly triple to approximately 1.5 billion, 16 percent of the worlds population. Although people are living longer, the quality of their lives are often compromised due to ill-health.
Areas covered. Of the conditions which compromise health as we age, obesity is at the forefront. Over half of the global older population were overweight or obese in 2010, significantly increasing the risk of a range of metabolic diseases. Although, it is well recognised excessive calorie intake is a fundamental driver of adipose tissue dysfunction, the relationship between obesity; intrinsic aging; and fat metabolism is less understood. In this review we discuss the intersection between obesity, aging and the factors which contribute to the dysregulation of whole-body fat metabolism.
Expert Commentary. Being obese disrupts an array of physiological systems and there is significant crosstalk among these. Moreover it is imperative to acknowledge the contribution intrinsic aging makes to the dysregulation of these systems and the onset of disease.
Keywords: Aging, obesity, fatty acid metabolism, inflammaging, endocrine system Introduction
The world population is aging ADDIN EN.CITE 2015464[1,2]46446427World Population Ageing Report2015United Nations20121251251255Aging and the Macroeconomy: Long-Term Implications of an Older PopulationThe National Academies Collection: Reports funded by National Institutes of Health2012Washington (DC)9780309261968
030926196123885367http://www.ncbi.nlm.nih.gov/pubmed/2388536710.17226/13465eng[1,2]. However, despite the dramatic rise in life expectancy global health is on the decline. Of the clinical problems whose prevalence is increasing, obesity, a chronic condition which is underpinned by an imbalance between energy ingested versus energy expended, is the most pronounced. Globally, more than half a billion adults aged 20 years and older are obese (BMI>30kg/m2) worldwide ADDIN EN.CITE WHO2015154[3]15415412WHOObesity and Overweight: Fact Sheet No 3112015WHOhttp://www.who.int/mediacentre/factsheets/fs311/en/[3]. In 2014, 39% of the worlds adult population were overweight (BMI >25kg/m2), with 13% classed as obese, a figure which has more than doubled since 1980 ADDIN EN.CITE WHO2015154[3]15415412WHOObesity and Overweight: Fact Sheet No 3112015WHOhttp://www.who.int/mediacentre/factsheets/fs311/en/[3]. This problem is amplified when the data for England is considered. In England it has been estimated ~80 % of males aged 55-64 years are overweight/obese, while and ~70% of females aged between 55-64 years are overweight/obese ADDIN EN.CITE 158[4]15815817Health Survey for England, 2014 [NS] 2015Avilable from: http://www.hscic.gov.uk/catalogue/PUB19295 [4] (Figure 1).
It is projected 2.8 million people die annually as a result of being overweight or obese ADDIN EN.CITE WHO2015154[3]15415412WHOObesity and Overweight: Fact Sheet No 3112015WHOhttp://www.who.int/mediacentre/factsheets/fs311/en/[3]. These fatalities are underpinned by the pathological footprint left by obesity, characterised by clinical conditions, which are the direct or indirect result of being overweight or obese. Such conditions include hypertension ADDIN EN.CITE Landsberg2013128[5]12812817Landsberg, L.Aronne, L. J.Beilin, L. J.Burke, V.Igel, L. 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S.Matteson, E. L.Davis, J. M., 3rdGabriel, S. E.Mayo Clinic, Rochester, MN 55905, USA.Contribution of obesity to the rise in incidence of rheumatoid arthritisArthritis Care Res (Hoboken)Arthritis care & researchArthritis Care Res (Hoboken)Arthritis care & researchArthritis Care Res (Hoboken)Arthritis care & research71-76512012/04/20AdultAgedArthritis, Rheumatoid/*epidemiologyCase-Control StudiesCohort StudiesComorbidityFemaleHumansIncidenceMaleMatched-Pair AnalysisMiddle AgedMinnesota/epidemiologyObesity/*epidemiologyReference ValuesRetrospective StudiesRisk Factors2013Jan2151-464x22514156Pmc3707391Nihms36190510.1002/acr.21660Nlmeng[9], dementia ADDIN EN.CITE ADDIN EN.CITE.DATA [10], and certain cancers, for example, breast ADDIN EN.CITE ADDIN EN.CITE.DATA [11], colorectal ADDIN EN.CITE Bardou2013135[12]13513517Bardou, M.Barkun, A. N.Martel, M.INSERM-Centre d'Investigations Cliniques Plurithematique 803 (CIC-P 803), CHU du Bocage, Dijon, France. marc.bardou@u-bourgogne.frObesity and colorectal cancerGutGutGutGutGutGut933-476262013/03/14Colorectal Neoplasms/diagnosis/epidemiology/*etiology/therapyFemaleHumansIncidenceMaleObesity/*complications/metabolism/therapyRisk FactorsTreatment Outcome2013Jun0017-57492348126110.1136/gutjnl-2013-304701Nlmeng[12], oesophageal ADDIN EN.CITE Chen2012136[13]13613617Chen, Q.Zhuang, H.Liu, Y.The association between obesity factor and esophageal canerJ Gastrointest OncolJournal of gastrointestinal oncologyJ Gastrointest OncolJournal of gastrointestinal oncologyJ Gastrointest OncolJournal of gastrointestinal oncology226-31332012/09/042012Sep2078-689122943013Pmc341853310.3978/j.issn.2078-6891.2012.026Nlmeng[13], pancreatic ADDIN EN.CITE Bracci2012137[14]13713717Bracci, P. M.Department of Epidemiology & Biostatistics, School of Medicine, University of California, San Francisco, California 94118-1944, USA.Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanismsMol CarcinogMolecular carcinogenesisMol CarcinogMolecular carcinogenesisMol CarcinogMolecular carcinogenesis53-635112011/12/14AdultAge Factors*Body Mass IndexFemaleHumansMaleObesity/*epidemiologyPancreatic Neoplasms/*epidemiology/mortalityRisk FactorsSex FactorsUnited States/epidemiology2012Jan0899-198722162231Pmc3348117Nihms28325810.1002/mc.20778Nlmeng[14] and gastric ADDIN EN.CITE Yang2009138[15]13813817Yang, P.Zhou, Y.Chen, B.Wan, H. W.Jia, G. Q.Bai, H. L.Wu, X. T.Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 37 Guo Xue Road, Chengdu 610041, Sichuan Province, China.Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studiesEur J CancerEuropean journal of cancer (Oxford, England : 1990)Eur J CancerEuropean journal of cancer (Oxford, England : 1990)Eur J CancerEuropean journal of cancer (Oxford, England : 1990)2867-7345162009/05/12Asia/ethnologyBody Mass IndexCohort StudiesFemaleHumansMaleObesity/complications/ethnologyOverweight/*complications/ethnologyRisk FactorsStomach Neoplasms/ethnology/*etiology2009Nov0959-80491942719710.1016/j.ejca.2009.04.019Nlmeng[15]. A feature of many of the diseases associated with obesity is the disruption of whole-body fatty acid metabolism; a metabolic system which is intimately coupled with adipose tissue function ADDIN EN.CITE Frayn2006139[16]13913917Frayn, K. N.Arner, P.Yki-Jarvinen, H.Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. keith.frayn@oxlip.ox.ac.ukFatty acid metabolism in adipose tissue, muscle and liver in health and diseaseEssays BiochemEssays in biochemistryEssays BiochemEssays in biochemistryEssays BiochemEssays in biochemistry89-103422006/12/06Adipose Tissue/*metabolismDiseaseExercise/physiologyFatty Acids/*metabolismHumansLipoprotein Lipase/metabolismLiver/*metabolismModels, BiologicalMuscle, Skeletal/*metabolismTriglycerides/metabolism20060071-1365 (Print)
0071-13651714488210.1042/bse0420089Nlmeng[16]. An elementary summary of the biological mechanisms which regulate fat metabolism is presented in figure 2. Briefly, ingested lipids are packaged intestinally and released into the blood stream as chylomicrons. Chylomicrons are hydrolysed by lipoprotein lipase (LPL), releasing free fatty acids (FFAs) into a fatty acid pool. FFAs are removed from the pool by muscle and hepatic tissue, where they are either oxidized or re-esterified. Hepatic triacylglycerides (TAGs) can be shuttled into the blood stream as a constituent of very low density lipoproteins (VLDLs). During periods of fasting, or as a result of sustained physical activity (PA), hormone sensitive lipase (HSL) is activated, and serves to mobilize FFAs by hydrolysing TAG found in adipose tissue ADDIN EN.CITE Frayn2006139[16]13913917Frayn, K. N.Arner, P.Yki-Jarvinen, H.Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. keith.frayn@oxlip.ox.ac.ukFatty acid metabolism in adipose tissue, muscle and liver in health and diseaseEssays BiochemEssays in biochemistryEssays BiochemEssays in biochemistryEssays BiochemEssays in biochemistry89-103422006/12/06Adipose Tissue/*metabolismDiseaseExercise/physiologyFatty Acids/*metabolismHumansLipoprotein Lipase/metabolismLiver/*metabolismModels, BiologicalMuscle, Skeletal/*metabolismTriglycerides/metabolism20060071-1365 (Print)
0071-13651714488210.1042/bse0420089Nlmeng[16]. Conversely during the fed state, adipose tissue fat storage is stimulated and fat mobilization suppressed by insulin. The activity of HSL is regulated by insulin, via an increase or decrease in the extent of phosphorylation of HSL, depending on the respective metabolic state. Clearly, the mechanisms which regulate fat metabolism are interdependent, and subtle alterations to them can disrupt fat metabolism. For instance, adipose tissue is a key regulatory hub within fat metabolism and many of the clinical manifestations associated with obesity are a direct consequence of the enlargement of and/or an increase in the number of cells found in adipose tissue, which is the result of excessive TAG deposition ADDIN EN.CITE ADDIN EN.CITE.DATA [17]. However, it is important to recognise that despite this, metabolically healthy obese individuals may not have these clinical manifestations ADDIN EN.CITE Gonalves2016168[18]16816817Gonalves, Carolina G.Glade, Michael J.Meguid, Michael M.Metabolically healthy obese individuals: Key protective factorsNutritionNutrition14-20321Morbid obesityVisceral obesityMetabolic syndromeInsulin resistanceMetabolically healthy obesity20161//0899-9007http://www.sciencedirect.com/science/article/pii/S0899900715003275http://dx.doi.org/10.1016/j.nut.2015.07.010[18].
The anatomical remodeling of adipose tissue results in a pathophysiology, characterised by the release of excess FFAs; a state induced as a result of enhanced lipolysis ADDIN EN.CITE ADDIN EN.CITE.DATA [19]. This pernicious metabolic state is often associated with immune system dysfunction and increased hormonal secretion. For instance, T2DM is regularly accompanied by a rise in inflammatory markers in tandem with hyperinsulinemia ADDIN EN.CITE Ye2013142[20]14214217Ye, J.Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. yej@pbrc.eduMechanisms of insulin resistance in obesityFront MedFrontiers of medicineFront MedFrontiers of medicineFront MedFrontiers of medicine14-24712013/03/09AMP-Activated Protein Kinases/metabolism*Diabetes Mellitus, Type 2/etiology/metabolism*Energy MetabolismFatty Acids, Nonesterified/metabolismHumansHyperinsulinism/metabolismInflammation/metabolismInsulin/*metabolismInsulin Resistance/*physiologyMetabolic Networks and PathwaysMitochondria/metabolism*Obesity/complications/metabolismRisk FactorsSignal Transduction2013Mar2095-021723471659Pmc3936017Nihms55613310.1007/s11684-013-0262-6Nlmeng[20]. Excess calorie intake is a key driver of adipose tissue dysfunction and concomitant metabolic dysregulation, however intrinsic aging also contributes significantly to the dysfunction of adipocytes and lipid metabolism more broadly ADDIN EN.CITE ADDIN EN.CITE.DATA [21,22]. In this paper we will discuss the relationship between whole body fat metabolism and the aging process. Our aim is to emphasize the contribution aging has to play in disrupting whole-body fat metabolism homeostasis and the contribution this makes to health in addition to obesity.
Dysregulation of Fatty Acid Metabolism with Age
During aging, body fat is redistributed from subcutaneous stores to the muscles and viscera ADDIN EN.CITE ADDIN EN.CITE.DATA [23-26]. Redistribution of fat to visceral adipose tissue is associated with a concomitant rise in plasma FFAs ADDIN EN.CITE Pararasa2016152[27]15215217Pararasa, ChathyanIkwuobe, JohnShigdar, ShahjahanBoukouvalas, AlexisNabney, Ian T.Brown, James E.Devitt, AndrewBailey, Clifford J.Bennett, Stuart J.