Embed Size (px)
Citation preview
Obesity and Inflammation
Nina BaileyBSc (hons) MSc PhD ANutr
Obesity statistics
In the UK, rates of obesity have increased by 30% in women, 40% in men and 50% in children within the last decade
A survey published in 2012 found that just over a quarter of all adults (26%) in England are obese with a further 41% of men and 33% of women classed as overweight
Obesity, particularly central (visceral) obesity, is the prominent risk factor for insulin resistance, metabolic syndrome and type II diabetes
In recent years, evidence has emerged that obesity is associated with inflammation that is directly linked to the development of insulin resistance
This webinar will discuss novel approaches for the treatment and prevention of insulin resistance and type II diabetes by targeting obesity-induced inflammatory processes
Why the weight gain?
Sedentary lifestyles, coupled with increased availability and consumption of energy-dense, nutrient-poor food that is rich in saturated fat and high in added sugar
Overloading the body with simple carbohydrates is known to be detrimental to health
Many of the high-carbohydrate foods common to Western diets produce a high glycaemic response that leads, over time, to obesity, increasing the risk of insulin resistance, metabolic syndrome and type II diabetes
In addition, today’s Western diets are characterised by increases in total fat, especially in saturated fat and omega-6 fatty acids, and decreases in omega-3 fatty acids in comparison to the fatty acid intake during evolution, to which our genes were programmed to respond
Obesity associated health risks:
Metabolic syndromeType II diabetesHypertensionStrokeHeart failureAtherosclerosisRenal failureLiver diseaseCancer
Adipose tissue used to be regarded as a silent and passive organ, storing excess energy as triglycerides and releasing energy as fatty acids
now recognised as an active endocrine organ affecting immunological processes and metabolism of the body
holds a host of immune cells including B cells, T cells, macrophages and neutrophils, with obesity influencing both the quantity and the nature of these immune cell subtypes secretes a wide variety of hormones, cytokines, chemokines and growth factors that influence metabolism, vascular and endothelial function, appetite and satiety, immunity, fertility, inflammation, tumour growth and many other body processes
A considerable effort has been made over the last two decades to elucidate the molecular factors responsible for obesity-associated co-morbidities; as a result, it is now well established that the key pathogenic mechanism is the presence of a ‘low-grade’ state of inflammation in the white adipose tissue
This low-grade inflammation, also known as metabolic-triggered inflammation or metainflammation, can be described as a long-term inflammatory response triggered by nutrients and calorie surplus
It involves a set of molecules/signalling pathways similar to those involved in classical inflammation, but in obesity-induced inflammation these molecules/signalling pathways have a dual role as inflammatory mediators as well as regulators of energy storage and metabolism
Direct link between inflammation and insulin resistance!
.Adipose tissue produces both pro- and anti-inflammatory factors including:
adipokines (cytokines, cell-signalling proteins, such as leptin, adiponectin and resistin) as well as other chemicals, such as tumour necrosis factor alpha (TNF-a) and interleukin 6 (IL-6)
Expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia, with large adipocytes exceeding the capacity for oxygen supply leading to hypoxia and cellular stress, leading to inflammation and the release of cytokines and other pro-inflammatory signals
Increased production of chemotactic factors (such as MCP-1) leads to the subsequent recruitment of a number of immune cells
Locally secreted chemokines attract pro-inflammatory macrophages into the adipose tissue where they then release cytokines that further activate the inflammatory program in neighbouring adipocytes, exacerbating inflammation
Adipose tissue macrophages are a prominent source of proinflammatory cytokines, such as TNF-α and IL-6, that can block insulin action
In obesity, the accumulation of infiltrating macrophages in adipose tissue and their phenotypic switch to M1-type dysregulated inflammatory adipokine production lead to obesity-linked insulin resistance
The increased production of pro-inflammatory adipokines (i.e. TNF,-α, IL-6, and MCP-1) in obese subjects directly correlate with the degree of glucose intolerance and insulin resistance
TNF-α interferes with glucose uptake by inhibiting phosphorylation of the insulin receptor
IL-6 reduces lipoprotein lipase activity, which likely results in both increased concentrations of circulating free fatty acids and insulin resistance
Catalan et al., 2013
Inflammation is an adaptive response to infection or tissue injury. Its purpose is to eliminate the injurious agent and remove damaged tissue components in an attempt to restore homeostasis
The onset of the inflammatory response is a well-known process that involves a complex interplay of soluble and cellular components characterised by changes in blood flow, an increase in permeability of blood vessels and migration of fluid, proteins and white blood cells from the circulation to the site of damage
Resolution of the inflammatory response is not a passive process but one that is coordinated by a complex regulatory network of cells and mediators that switch inflammation off in a specific time-limited manner
Resolvins are potent anti-inflammatory and pro-resolving mediators that are endogenously generated from omega-3 fatty acids that act as ‘stop-signals’ of the inflammatory response, promoting the resolution of inflammation
A deficit in the production of these endogenous anti-inflammatory signals will result in what is termed silent inflammation
Insulin resistance is the physiological condition in which cells fail to respond to the normal actions of the hormone insulin
• The body produces insulin, but the cells
become resistant, leading to hyperglycaemia
• Beta cells in the pancreas subsequently
increase their production of insulin,
further contributing to hyperinsulinaemia
• If undetected, insulin resistance can
lead to the development of
type II diabetes
Winer & Winer 2012
The pathogenesis of obesity-related insulin resistance and visceral fat inflammation
Weight loss improves insulin sensitivity and inflammatory markers
van Kruijsdijk et al., 2009
Diet and exercise for weight loss?
Current recommendations from most public health bodies for reducing body fat are based on increasing physical activity and eating a healthy & balanced diet
Reductions in body weight (calorie restriction, liposuction, or bariatric surgery) correlate with significant reductions in inflammatory markers and improved insulin sensitivity
However, many people have difficulty complying with these lifestyle changes, particularly over the longer term
For example: 6 studies directly comparing diet and exercise vs diet alone, with an active intervention period ranging between 10 and 52 weeks across studies
Diet associated with exercise produced a 20% greater initial weight loss (13 kg vs 9.9 kg)
The combined intervention also resulted in a 20% greater sustained weight loss after 1 y (6.7 kg vs 4.5 kg) than diet alone
In both groups, almost half of the initial weight loss was regained after 1 year(Curioni & Lourenco 2005)
More strategies are needed!!
Omega-3 for weight loss?
In young, overweight men, the inclusion of either lean or fatty fish, or fish oil as part of an energy-restricted diet resulted in approximately 1 kg more weight loss after 4 weeks, than did a similar diet without seafood or supplement of marine origin (Thorsdottir et al., 2007)
A dose-response relationship between cod consumption and weight loss during an 8-week energy restriction diet is found and 5 x 150 g cod/week results in 1.7 kg greater weight loss in young overweight or obese adults than an isocaloric diet without seafood (Ramel et al., 2008)
Weight-loss diets that include oily fish offer more favourable outcomes on blood lipid levels than diets without fish or fish oil (Gunnarsdottir et al., 2008)
Seafood consumption, weight loss and inflammatory markers
8-week intervention trial, 324 subjects (aged 20-40 years, body mass index 27.5-32.5 kg/m(2)
Randomised to one of four energy-restricted diets (-30% relative to estimated requirements):
Salmon (3 x 150 g/week, 2.1 g LC n-3 PUFA per day)Cod (3 x 150 g/week, 0.3 g LC n-3 PUFA per day)Fish oil capsules (1.3 g LC n-3 PUFA per day) Control (sunflower oil capsules, no seafood)
Body weight, high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), glutathione reductase and prostaglandin F2 alpha (PGEF2alpha) were measured at baseline and end point
All subjects experienced weight loss, with salmon consumption the most effective with three of the four measured inflammation markers decreasing significantly in the salmon group (Ramel et al., 2010)
.
Relationship between omega-3 index and obesity
Polyunsaturated fatty acids (PUFA) are known to beneficially influence fat metabolism and there are numerous studies in animal models of obesity showing that consumption of PUFA, particularly the long-chain omega-3 PUFA, can increase fat loss and counteract adiposity (Buckey & Howe 2009)
Higher plasma levels of total omega-3 PUFA are associated with a healthier BMI, waist circumference and hip circumference (Micallef et al., 2009)
Correlations between omega-3 index and BMI have been reported in both adults (with this association appearing to be gender specific) (Howe et al., 2014) and children (Burrows et al., 2011)
Is there room for clinical application using omega-3?
Insulin and desaturase activity
• Patients with obesity or type II diabetes are characterised by a different fatty acid composition of serum lipids as compared to healthy lean subjects
• Insulin resistance is associated with measures of desaturase activities since there exists evidence that there are changes of the fatty acid desaturase activities under insulin resistant conditions
• Such an abnormal fatty acid profile in healthy subjects predicts further development of type II diabetes
• Patients with type II diabetes exhibit higher plasma AA levels, higher delta-5 desaturase activity index (indicating poor desaturase activity) , and higher AA to EPA ratios than healthy controls
(Vessby et al., 2002; Krachler et al., 2008; Imamura et al., 2014)
Resoleomics - the process of inflammation resolution In
flam
mat
ory
resp
onse
Initiation Resolution Termination
PGE2
LTB4
Eicosanoid switch Stop signal
Time
Pro-inflammatory reduced
Anti-inflammatory increased
Source: Bosma-den Boer et al., 2012
.Omega-3 and insulin sensitivity
Low omega-3 is common in insulin resistant individuals
Omega-3 index is a useful biomarker of cardiovascular health
Higher omega-3 index is associated with increased insulin sensitivity, lower omega-6 to omega-3 ratio and lower CRP levels (in middle-aged overweight men) (Albert et al., 2014)
Dietary intervention with omega-3 fatty acids (as both fish and fish oil) increases the omega-3 index and improves insulin sensitivity and decreases CRP and IL-6 (Tsitouras et al., 2008)
High AA to EPA ratio is associated with insulin resistance
Significant correlation between AA to EPA ratio and insulin resistance observed in subjects with metabolic syndrome (Yanagisawa et al., 2010)
High AA to EPA ratio, a direct biomarker of inflammatory status, is associated with insulin resistance, with visceral fat accumulation correlating significantly with serum AA to EPA ratio
Subjects with visceral fat accumulation ≥100 cm2 had higher serum AA to EPA ratio (but not DHA to AA or [EPA+DHA] to AA) and more likely to have metabolic syndrome and history of CAD, compared to those with visceral fat accumulation <100 cm2 (Inoue et al., 2013)
“The balance of AA to EPA by lifestyle modification and medication (such as EPA-based medications) could be useful in reducing the prevalence of the metabolic syndrome and atherosclerosis” (Inoue et al., 2013)
Omega-3 intake and diabetes
Cohort study, involving around 2000 men aged 42 to 60 years from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD), free of diabetes at baseline in 1984–1989
Serum omega-3 PUFA, dietary intake (4-day food diary) and hair mercury levels used as biomarkers for exposure
Incidence of type II diabetes was assessed by self-administered questionnaires and glucose tolerance tests (at 4, 11, and 20 years from baseline) and by record linkage to hospital-discharge registry and the reimbursement register on diabetes medication expenses
After an average follow-up of 19.3 years, 422 men (19.2%) had developed diabetes, and those in the highest quartile of serum long-chain omega-3 PUFA concentrations (>5.33% total serum fatty acids) had a 33% lower risk for incident type II diabetes compared with men in the lowest quartile (P for trend = .01)
Virtanen et al., 2014
There is increasing evidence suggesting that dietary omega-3 may improve insulin sensitivity or reduce the incidence of type II diabetes
Epidemiological studies have linked both higher dietary and plasma omega-3 PUFA concentrations with lower risk of diabetes
(Villegas et al., 2011; Djoussé et al., 2011; Virtanen et al., 2014)
Fish consumption is associated with lower inflammatory markers levels, among healthy adults (compared to non-fish consumers, those who consumed >300 g of fish per week had on average 33% lower CRP, 33% lower IL-6, 21% lower TNF-α)
(Zampelas et al., 2005)
Fish consumption and the metabolic syndrome
Cross-sectional study conducted on 420 Iranian female adults with usual fish consumption was assessed using a dish-based semi quantitative food frequency questionnaire (FFQ)
The prevalence of metabolic syndrome was 8.2%
Mean daily intake of fish was 14.4 g per day, individuals in the highest tertile of fish intake were 65% less likely to have metabolic syndrome than those in the lowest tertile (odds ratio: 0.35; 95% confidence interval (CI): 0.14-0.88)
After adjustment for potential cofounders, high fish intake was inversely associated with hypertriglyceridaemia (odds ratio: 0.11; 95% CI: 0.01-0.85), low high-density lipoprotein cholesterol (odds ratio: 0.57; 95% CI: 0.19-0.89) and elevated blood pressure (odds ratio: 0.23; 95% CI: 0.14-0.89)
Zaribaf et al., 2014
Obesity, insulin resistance and the metabolic syndrome
Levels of saturated fatty acids are significantly higher and EPA levels significantly lower in obese subjects both with and without insulin resistance compared to controls (p<0.001 for both) (Gunes et al., 2014)
Subjects with metabolic syndrome have been shown to possess tissue and plasma fatty acid profiles characterised by a relative predominance of saturated fatty acids and omega-6 polyunsaturated fatty acids, with corresponding low levels of long-chain omega-3 polyunsaturated fatty acids
This fatty acid pattern appears to confer a higher risk of both diabetes and coronary heart disease (CHD) events
.
30 patients with coronary artery diseases – six month study
Control group (n=15, conventional therapy)EPA group (n=15, conventional therapy plus purified EPA 1800 mg/day)
Compared to control group, treatment with EPA:
Significantly reduced the AA to EPA ratioSignificantly reduced both epicardial adipose tissue and
abdominal visceral adipose tissue volumesNon-significantly reduced abdominal subcutaneous adipose tissue volumes Significantly reduced CRP levels Significantly reduced TG
Effects of eicosapentaenoic acid treatment on epicardial and abdominal visceral adipose tissue volumes in patients with coronary artery disease
(Sato et al., 2014)
Omega-3 Fatty Acids Reduce Adipose Tissue Macrophages in Human Subjects With Insulin Resistance
Non-diabetic subjects with the metabolic syndrome and insulin resistance were randomised to either fish oil (4 g/day) or placebo for 12 weeks
Although there were no changes in insulin sensitivity, adipose tissue macrophages were decreased and adipose capillaries increased in the fish oil-treated subjects (as determined by adipose biopsy), along with a decrease in adipose and plasma MCP-1
In addition, omega-3 fatty acids suppressed the up-regulation of adipocyte MCP-1 that occurred when adipocytes were co-cultured with macrophages
MCP-1 contributes to macrophage infiltration into adipose tissue and to insulin resistance in obesity
Blocking or reducing MCP-1 activity is a potential therapeutic target for reducing the risk of developing insulin resistance
Spencer et al., 2013
.
In vitro and animal studies show us that:
Omega-3 fatty acids induce a shift for M1 pro-inflammatory macrophage state to a more favourable M2 state
inhibit a number of signalling pathways that suppress adipose tissue inflammation
reduce levels of a number of pro-inflammatory products (CRP, TNF-α, MCP-1, IL-6 etc)
activate PPAR-γ thereby decreasing the expression of molecules (such as TNF-α) that cause insulin resistance
inhibit adipocyte differentiation
increase anti-inflammatory adiponectin secretion
restore insulin sensitivity
(Sato et al., 2014)
Biomarkers for personalising omega-3 fatty acid dosing
Omega-3 index an early cardiovascular risk indicatorOmega-6 to omega-3 ratio an established marker of long-term health and chronic illnessAA to EPA ratio a measure of ’silent’ or chronic inflammation
A personalised plan aims to achieve:An omega-3 index of more than 8% An omega-6 to omega-3 ratio of between 3 and 4An AA to EPA ratio of between 1.5 and 3
Base line 4 months ∆ change OutcomeOmega-3 index 3.50 5.98 2.48 Undesirable to desirable AA to EPA ratio 8.52 3.54 4.98 Suboptimal to acceptable
Case study – subject X
Improvement in both AA to EPA ratio and omega-3 index after 4 months supplementation with 1.5g EPA (Pharmepa RESTORE)
.
Using the Opti-0-3 in practice
Identify those at risk
Management tool for those suspected to be at risk of developing, or known to have metabolic syndrome/insulin resistance
Management tool for those co morbidities related to insulin resistance
.
Flock et al., 2014
RBC membrane content of AA versus circulating TNF-α and IL-6 concentrations in healthy adults
Managing the AA to EPA ratio/omega-3 index via EPA supplementation
Individuals with high AA to EPA ratio and low omega-3 index are at a higher risk of developing insulin resistance and therefore co-morbidities associated with insulin resistance
Levels of pro-inflammatory products in obese subjects, directly correlate with the degree of glucose intolerance and insulin resistance
Treating with omega-3 improves pro-inflammatory profile patterns in both healthy and insulin resistant individuals
Treating with omega-3 also lowers elevated cholesterol, lipids and blood pressure which are factors related to insulin resistance
Treatment is important, but intervention as prevention is important for long-term health
Useful addition to weight loss regimes
References
Albert, B. B., J. G. Derraik, et al. (2014). "Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men." Scientific reports 4: 6697.
Bosma-den Boer, M. M., M. L. van Wetten, et al. (2012). "Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering." Nutr Metab (Lond) 9(1): 32.
Buckley, J. D. and P. R. Howe (2009). "Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids." Obesity reviews : an official journal of the International Association for the Study of Obesity 10(6): 648-659.
Buckley, J. D. and P. R. Howe (2010). "Long-chain omega-3 polyunsaturated fatty acids may be beneficial for reducing obesity-a review." Nutrients 2(12): 1212-1230.
Burrows, T., C. E. Collins, et al. (2011). "Omega-3 index, obesity and insulin resistance in children." Int J Pediatr Obes 6(2-2): e532-539.
Catalan, V., J. Gomez-Ambrosi, et al. (2013). "Adipose tissue immunity and cancer." Frontiers in physiology 4: 275.
Curioni, C. C. and P. M. Lourenco (2005). "Long-term weight loss after diet and exercise: a systematic review." International journal of obesity 29(10): 1168-1174.
References
Djousse, L., M. L. Biggs, et al. (2011). "Plasma omega-3 fatty acids and incident diabetes in older adults." The American journal of clinical nutrition 94(2): 527-533.
Djousse, L., J. M. Gaziano, et al. (2011). "Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes." The American journal of clinical nutrition 93(1): 143-150.
Flock, M. R., A. C. Skulas-Ray, et al. (2014). "Effects of supplemental long-chain omega-3 fatty acids and erythrocyte membrane fatty acid content on circulating inflammatory markers in a randomized controlled trial of healthy adults." Prostaglandins Leukot Essent Fatty Acids 91(4): 161-168.
Howe, P. R., J. D. Buckley, et al. (2014). "Relationship between erythrocyte omega-3 content and obesity is gender dependent." Nutrients 6(5): 1850-1860.
Imamura, S., T. Morioka, et al. (2014). "Plasma polyunsaturated fatty acid profile and delta-5 desaturase activity are altered in patients with type 2 diabetes." Metabolism: clinical and experimental 63(11): 1432-1438.
Inoue, K., K. Kishida, et al. (2013). "Low serum eicosapentaenoic acid / arachidonic acid ratio in male subjects with visceral obesity." Nutr Metab (Lond) 10(1): 25.
Jung, U. J. and M. S. Choi (2014). "Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease." International journal of molecular sciences 15(4): 6184-6223.
References
Krachler, B., M. Norberg, et al. (2008). "Fatty acid profile of the erythrocyte membrane preceding development of Type 2 diabetes mellitus." Nutr Metab Cardiovasc Dis 18(7): 503-510.
McArdle, M. A., O. M. Finucane, et al. (2013). "Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies." Frontiers in endocrinology 4: 52.
Micallef, M., I. Munro, et al. (2009). "Plasma n-3 Polyunsaturated Fatty Acids are negatively associated with obesity." The British journal of nutrition 102(9): 1370-1374.
Ramel, A., J. A. Martinez, et al. (2010). "Effects of weight loss and seafood consumption on inflammation parameters in young, overweight and obese European men and women during 8 weeks of energy restriction." European journal of clinical nutrition 64(9): 987-993.
Sato, T., T. Kameyama, et al. (2014). "Effects of eicosapentaenoic acid treatment on epicardial and abdominal visceral adipose tissue volumes in patients with coronary artery disease." Journal of atherosclerosis and thrombosis 21(10): 1031-1043.
Spencer, M., B. S. Finlin, et al. (2013). "Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance." Diabetes 62(5): 1709-1717.
Thorsdottir, I., B. Birgisdottir, et al. (2009). "Fish consumption among young overweight European adults and compliance to varying seafood content in four weight loss intervention diets." Public health nutrition 12(5): 592-598.
References
Thorsdottir, I., H. Tomasson, et al. (2007). "Randomized trial of weight-loss-diets for young adults varying in fish and fish oil content." International journal of obesity 31(10): 1560-1566.
Tsitouras, P. D., F. Gucciardo, et al. (2008). "High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults." Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 40(3): 199-205.
van Kruijsdijk, R. C., E. van der Wall, et al. (2009). "Obesity and cancer: the role of dysfunctional adipose tissue." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 18(10): 2569-2578.
Vessby, B., I. B. Gustafsson, et al. (2002). "Desaturation and elongation of Fatty acids and insulin action." Annals of the New York Academy of Sciences 967: 183-195.
Villegas, R., Y. B. Xiang, et al. (2011). "Fish, shellfish, and long-chain n-3 fatty acid consumption and risk of incident type 2 diabetes in middle-aged Chinese men and women." The American journal of clinical nutrition 94(2): 543-551.
Virtanen, J. K., J. Mursu, et al. (2014). "Serum omega-3 polyunsaturated fatty acids and risk of incident type 2 diabetes in men: the Kuopio Ischemic Heart Disease Risk Factor study." Diabetes Care 37(1): 189-196.
Winer, S. and D. A. Winer (2012). "The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance." Immunology and cell biology 90(8): 755-762.
