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Health and Disease

Obesity The world health organisation (WHO): “overweight and obesity is the abnormal or excessive fat accumulation that presents a risk to health”

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It’s not so much abnormal now as obesity is becoming more common – it’s just unhealthy

BMI = weight (kg)/ height (m)2  Adopted for international use but isn’t accurate as its doesn’t represent health as muscle weighs more than fat therefore a short muscly person will be classed as obsess when they aren’t.  The cut off points: chronic disease and mortality if you are outside the regions  Only relevant for certain age ranges  J-shaped curve

Key Facts 1) Worldwide obesity has doubled since 1980 2) 2008: 1.4 (33%) billion adults were overweight (200m m and 300m f were obese – 11%) 3) 65% of the population live in countries were obesity kills more than underweight 4) 2011: 40m children under 5 were over weight 5) Obesity IS PREVENTABLE

Causes Chronic positive energy intake causes weight gain A balance between input and output contribute to weight maintenance Increase output (energy expenditure) to input contributes to weight loss Chronic + energy input  Genes  Environment/lifestyle  Epigenetics (heritable changed in gene function but not changes in the DNA sequence)  Microbiome (the microorganisms in a particular environment – our bodies) We have created an “obesogenic” environment yet we are NOT evolved to live in one FTO (fat mass and obesity associated gene)

Health and Disease

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Minor allele increases BMI by 0.39 (1.130g of body weight) increasing risk of obesity by 1.20-fold Effects younger adults the most Thought to subtle change food intake and preferences // nutrient sensing, regulation of mRNA translation and general growth 40-70% variation in obesity susceptibility – genetic Less than 75 obesity susceptibility loci

Risks Metabolic consequences High risk  Type 2 diabetes  Gall bladder disease  Hypertension  Dyslipidaemia  Insulin resistance  Atherosclerosis Moderate risk  CHD  Stroke  Gout/hyperuricaemia Slight risk  Cancer  Reproductive complications/abnormalities  Polycystic ovaries  Skin complications  Cataract Weight High risk  Sleep apnoea  Breathlessness  Asthma  Social isolation/depression  Daytime sleepiness/fatigue Moderate risk  Osteoarthritis  Respiratory disease  Hernia  Psychological problems (depression etc.) Slight risk  Varicose veins  Musculoskeletal problems  Bad back  Stress  Oedema/cellulitis England – adult obesity prevalence from 1993 to 2013

Health and Disease

 ♂ 13.2 → 26% / ♀ 16.4 → 23.8 % (NHS – digital data, 2015) How to address obesity The WHO solution: making healthy choices easy choices  Spearheading a series of expert and technical consultations  Promoting awareness: campaigns, policies  Highlight obesity as a ‘social and environmental disease’  Help develop strategies healthy choices easy choices

Alternate/complementary solutions Pharmacological agents:  Reducing intake (target appetite, reward centres) – most plausible  Reduce uptake (absorption) – ethical implications?  Increases metabolic rate (promote brown adipose tissue) Surgical solutions  Reduce food intake (gastric band)  Reduce food uptake

Ectopic Fat: promotes disease

The portance of fat/adipose tissue Too little  lipodystrophy Too much  obesity  We need the right amount to be healthy

Adipose Tissue

Health and Disease Adipocytes – 30—50% Preadipocytes (fibroblasts) Endothelial cells Macrophages/blood cells Pericytes White Adipose Tissue (WAT)  Large, unilocular lip droplets  Small mitochondria, disorganised  No uncoupling protein 1 (UCP1)  Energy storage (neutral lipids)  Not all WAT is the same, therefore it’s all about the location of it  Better/healthier to be a pear shape and to store excess fat on your bum -Omental (visceral) -Subcutaneous In humans

Brown Adipose Tissue (BATS)  Small, multilocular lipid droplets  Large mitochondria, well developed  Express UCP1  Thermogenesis (heat production) In humans  Determined by uptake of fluorodeoxyglucose positron emission tomography (FDP PET) combined with computed tomography  Found in areas associated with large blood vessels – therefore easier to warm the body up as BAT produces heat Adipocyte turnover  Evidence from animals that adipocyte number changes during the lifetime of the animal Used to think you kept the same adipocytes throughout your life  cells got bigger and smaller Studies Carbon dating  Russians fired off bombs and that caused trace elements of carbon in DNA  therefore calculate life time of fat cells (half-life)

Health and Disease

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10% of fat cells renewed annually at all adult ages and levels of BMI  apoptosis/generation rate is not altered in early onset obesity  High turnover  new therapeutic targets which we should be able to intervene for intervention in obesity  Thought it would be good to block new generation of adipocytes // not a good strategy  Necrosis in inflamed adipose tissue Adipogenesis: proliferation and terminal differentiation of preadipocytes (multipotent stem cells)  adipocytes  strong genetic predisposition  Highly controlled  leads to the generation of mature, insulin responsive, lipid filled adipocytes  Insufficient adipogenesis  leads to insulin resistance and type 2 diabetes Coordinated Adipose Tissue expansion is required for maintenance of metabolic homeostasis in obesity Adipocyte hypertrophy – ANGRY (diabetes, CVD, Stroke, Cancer)  inflamed adipose tissue Adipocyte hyperplasia – HAPPY (metabolically healthy obese MHO)  maintains normal levels of system and tissues, may still have physicality’s (10-25% of obese individuals)  Characterised by inaprop or aprop expansion of adipose tissue Adipose tissue Endocrine: Leptin, Adiponectin, Resitin, Visfatin, Corticosteriods, Sex steroids Immune: TNFalpha, IL-6  bad, markers of obesity, Complements, ASP, MCP1 Metabolic: Free fatty acids, PPARY ligands (lipids) Cardiovascular: PAI-1, Renin-Angiotensin Adipose tissue is like a bank  it produces all of these factors (cytokine-like factors produced predominantly) Regulation of fat mass – lessons from parabiosis experiments 1978  Obese and Diabetic mice fused with normal mice, connecting their blood supplied (shared nutrients and hormones) and left them  Obese mouse lost weight  the normal mouse was putting something into the blood of the obese mouse to stop it feeding – obese mouse missing the satiety factor  Normal mouse connected to diabetic mouse died of starvation, even though food was there  diabetic mouse resistant to the satiety factor, diabetic gene encodes for the obese gene, so diabetic produced lectin which was going into the normal mouse which tells the mouse not to eat !!!!!!!!!LECTIN 1994!!!!!!!!!!! Obesity = lectin resistance so can’t treat it with lectin Monogenic cause of obesity  Leptin deficient  sequenced leptin gene (DELETION OF C) therapeutic strategy was to give them lectin therefore they could be given the treatment

Health and Disease

Leptin Congenital Leptin Deficiency  Essential for regulation of body weight  Deficiency’s = intense hyperphagia, food-seeking and aggressive behaviour when food is denied  Increased hunger and impaired satiety (linked to areas of the brain associated with pleasure and reward – don’t get it so keep seeking)  Abnormalities in thyroid function  Increased fat mass (compared to equally obese subjects) (heterozygous humans  RARE)  Failure of normal pubertal developmental/infertility  Increased frequency of infection and abnormalities in T cell function (immune failure) Recombinant leptin therapy has beneficial effects  Normalisation of food intake and reduced hunger  No major effect on basal metabolic rate  Normalisation of thyroid function  Preferential loss of fat mass (compared to weight loss in regular obese individuals)  Permits progression of puberty  Normalisation of T cell function

Leptin summary Peptide hormone (adipokine) secreted by adipocytes Signals energy stores / availability to brain A starvation hormone implicated in obesity Has effects on CNS (hypothalamus) and in the periphery Reduces appetite, increases BMR & activity and regulate fertility and immunity Levels increase in obesity (positive correlation with fat mass) Leptin resistance occurs in obesity Effects are mediated by a cell surface receptor

Adiponectin   

Discovered in 1995 Produced only in adipocytes // circulates in high conc. Production is decreased in obesity // increase in weight loss -further reduced in insulin resistance and CVD

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Anti-diabetic (insulin sensitizer) Anti-inflammatory Anti-atherogenic Mutations associated with insulin resistance/type 2 diabetes Acts via two receptors AdipoR1 & AdipoR2

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Health and Disease

 In obesity adipose tissue becomes pro-inflammatory  low grade, chronic inflammation contributes to systemic insulin resistance - a precursor for T2D

Obesity Summary        

Two types of adipose tissue - Brown (BAT) and White (WAT) Adipocytes - major constituent (30-50%) Dogma until recently - Humans born/die with ‘X’ adipocytes Now know adipocyte number is dynamic Regulated in line with net energy balance Acquisition - proliferation & differentiation (Adipogenesis) Loss - apoptosis & necrosis Adipocytes secrete a number of biologically active molecules - Adipokines - regulate all aspects of our physiology through autocrine, paracrine and endocrine effects - Dysregulation of adipokines contributes to development of obesity associated diseases

Questions Why do some people become obese? What strategies can be used to reduce obesity? Name some common obesity-related metabolic diseases Name (& discuss) some of the factors that contribute to the development of these obesity-related diseases? What is adipogenesis? What are adipokines? What happens to circulating leptin levels in obesity? What happens to circulating adiponectin levels in obesity? Name some pro-inflammatory adipokines that are increased in obesity What is meant by the term ‘insulin resistance’ and why is it important?...