Obesity & metabolic syndrome

A/prof. Barbara Ukropcová, MD, PhD

barbara.ukropcova@gmail.com

Institute of Pathophysiology, FMCU

& Biomedical Research Center, Slovak Academy of Sciences

4-2020

What are the causes of chronic

civilisation diseases?

Age + Genes + x + y + z...

Modifiable risk factors (according to WHO)

X = overweight / obesity

Y = physical inactivity

Z = smoking

Nature. 2008 July 24; 454(7203): 463–469.

Visceral obesity

Dysfunctional

adipose tissue &

skeletal muscle

Lipotoxicity

Chronic

inflammation

Insuline resistance

Metabolic

syndrome Despres, Lumieaux, Nature 2006

65% global mortality Blair SN, Archer E et al, 2012

Independent risk factors of chronic disease:

USA 32,20%Australia 16,40%Canada 15,30%Slovakia 14,30%Czech Republic 15,05%Hungary 18,80%

OBESITY

BMI>30 [kg/m2]

www.iuns.org/features/obesity/tabfig.htm

Projected Prevalence of Obesity in Adults

BMI>30Height weight

[cm] [kg]

150 > 67

160 > 76

170 > 86

180 > 97

190 > 108

OBESITY STATISTICS

WORLD HEALTH ORGANISATION (FACT SHEET N°311)

• Worldwide obesity has nearly doubled since 1980.

• In 2008, > 1.4 billion adults, 20 and older, were overweight. Of

these, > 200 million men & nearly 300 million women were

obese.

• 35% of adults aged 20 and over were overweight in 2008, and

11% were obese.

• 65% of the world’s population live in countries where

overweight / obesity kills more people than underweight.

• Overweight / obesity are 5th leading risk for global deaths.

At least 2.8 million adults die each year as a result of being

overweight or obese.

• 44% of diabetes, 23% of ischaemic heart disease and 7% to

41% of certain cancers are attributable to overweight / obesity.

• > 40 million children < 5yrs old were overweight in 2011.

• Obesity is preventable!

Social environment Infrastructure

Obesogenic environment

Obesogenic behaviour

• overeating

• sedentarism

• physical inactivity

Biological predisposition

Energy intake and

expenditure, adipogenesis,

metabolism

Positive energy balance

Increased body weightAdapted from Bouchard & Katzmarzyk, 2010

Ethiopathogenesis

of obesity:Obesogenic environment

supports acceptance and

maintenance of obesogenic

behavior. Obesogenic lifestyle /

behavior interacts with

biological predisposition,

which has a high prevalence in

the population.

Etiopathogenic classification of obesityCommon obesity > 90 % , interaction of obesogenic environment and genetic predisposition

Obesity in endocrinopathies

hypothyroidism, Cushing syndrom, GH deficiency...

Pharmacotherapy and obesity

Drugs with an impact on the mechanisms of regulation of body weight or differentiation and

accumulation of lipids in the adipose tissue

Obesity in CNS afflictions

Damage to the centers of food intake regulation

Syndroms associated with obesity

Very rare inheritable diseases, associated with a typical spectrum of inborn defects

Monogenic obesity

Very rare, based on the mutation of a single gene and associated with obesity in an early

childhood

Obesity from other causes

Persistant organic pollutants, inadequate sleep, adenoviral infection, ...

Obesity

Genes„Thrifty“ genotype –

Energy supplies

epigenetics(in utero, early childhood)

Lifestyle

(caloric excess,

physical inactivity)

Genes and the environment

Monogenic forms of obesityare very rare. The cause of obesity is the mutation

in a single gene

• Leptin deficiency – ob gene

• Leptin receptor mutation

• POMC

• MC4R receptor for melanocortin 4

• Prohormon convertase I

Hypothalamic regulation of food intake

Causes of obesity epidemics?

54.7 (38.4 to 72.8) g/d

10.2% total caloric intake

the highest consumption in the group of

adolescents 12-18 years old

Bray GA. Fructose-how worried should we be? Medscape J Med. 2008 Jul 9;10(7):159.

500x increase !!!

A decrease in work-related

energy expenditure

Church TS et al., Trends over 5 Decades in U.S. .

PLoS One. 2011

Adapted from Avena N. a spol. 2012

An increase in the portion size

Adapted from Schwartza, Nature 2002

IL-6

?

adiponectin

Adipose

tissue

skeletal

muscle

Growth

hormone

Energy balance: A crosstalk of tissues and organs

involved in energy homeostasis

Črevný mikrobióm:

• zmena zloženia

• zmena fermentácie

• zvýšenie získavania

energie z potravy

liver

short chain fatty acids

inflammation

Adipose tissue

Synthesis of TAG

inflammation

Skeletal muscle

Oxidation of FFA

Intestinal epithelium

Permeability

PYY/GLP1 from L

cells

brain

satiety

Gut microbiota:

• changes in composition

• changes in fermentation

• an increased acquisition of

energy from food

The composition

of intestinal

microbiome

Influences body

weight and

metabolism

Sleep and obesity

short average long

sleep

short average long

sleep

Adapted from Chaput JP, 2008

Changes in body weight and

waist circumference are

compared in individuals with a

short and longer average

sleep time during 6 year

follow-up.

Pharmacotherapy & obesity

• thyreostatics

• Beta-blockers

• dopaminergic blockers (neuroleptics...)

• specific antiepileptics (valproate)

• psychopharmacs: antidepressant, lithium

• estrogens, medroxyprogesteron

• antidiabetics (insulin, sulfonylurey and TZD)

• corticoids

Pathophysiology and changes in the

adipose tissue

Adipose tissue: composition

• Adipocytes represent about 50% of all cell types

in the adipose tissue

• Vascular elements, preadipocytes, fibroblasts,

macrophages, mesenchymal cells…

- subcutaneous

- visceral

- white

- brown

Types of adipose tissue

Cinti, 2001

18FDG-PET

Lean at 25oC Lean at 16oC (2h) Obese at 16oC (2h)

Brown adipose tissue in adult humans is visualized upon cold exposure

Adipose tissue as an endocrine organBiosynthetic Activites of Adipocytes

adipokines:

proteins secreted by adipocytes

- leptin

- adiponectin

- resistin

- visfatin

- zinc-α2-glycoprotein

- interleukin 6

- tumor necrosis factor α

- omentin

- apelin

• a product of ob gen

• a suppressor of food intake

• increases fat oxidation

– ob/ob mice

– db/db mice

Leptin

(http://thegreatromance.wordpress.com/2009/03/07/)

Adiponectin

• produced by adipocytes (described in 1996)

• antiinflammatory, anti-T2D and anti-AS effects

• low levels implicated in a MS

• receptors: AR1 skeletal muscle; AR2 liver,

macrophages

• inverse correlation with BMI and visceral adipose

tissue

• increased by PPARgama agonists and fibrates

ObesityAn excessive accumulation of adipose tissue

Food

intake

Energy

expenditure

• REE: 1kcal/kg weight/h

• METs: fold increase of

REE

• Dietary diary

• Nutritive anamnesis

Types of obesity:

apple and pear

• intraabdominal

adipose tissue

• high risk of

T2D and CVD

• subcutaneous

adipose tissue

• low risk of

T2D and CVD

Ectopic accumulation of

fat

Despres, Lumieaux, Nature 2006

Smoking

Genetic predisposition

Maladaptive response to stress

Positive energy balance

Normal adiposity

Increased

energy

intake

Decreased

physical

activity

Normal

metabolic profile

Subcutaneous obesity

„healthy“ adipose tissue

Visceral obesity

Dysfunctional adipose t

Changed

metabolic profile

Metabolic

syndrom

HOW the FAT is stored?

WHERE the FAT is stored? …spill over of fat into the liver, muscle, pancreas, heart, lung*

… full bucket hypothesis

Unger RH, et al., Lipid homeostasis, lipotoxicity and the metabolic syndrome Biochim Biophys Acta. 2010; 1801:209-14

*Foster DJ, et al., Fatty diabetic lung: altered alveolar structure and surfactant protein expression. Am J Physiol. 2010; 298:L392-403

Obesity ≠ metabolic disease

The effect of exercise on NAFLD

Extrémny prípad

ektopického

ukadania lipidov

v pečeni (A)

v spojení s viscerálnou

obezitou (B).

Účinok 3 mesiacov

silového cvičenia na

obsah lipidov

v pečeni (C)

stanovenom pomocou

MR spektroskopie. (Ukropcová, Ukropec,

Klinická obezitológia,

Krahulec a spol 2013).

The tissue / cellular / molecular mechanisms

behind the negative impact of obesity on health

Lipotoxicity

Schenk S, et al., Insulin sensitivity: modulation by nutrients and inflammation Journal of Clinical Investigation. 2008; 118:2992-3002

poškodenie bunky

zápalová odpoveď

LPC, AA

Inflammation of adipose tissue in obesity

MAC NC

Kadowaki et al., 2006

Insulin resistant phenotype of liver & skeletal muscle

is associated with adipose tissue qualities

obese adipose tissue

lean adipose tissue

Glucose utilization

Glucose production

CRP, SAA,

Insulin secretion

Beta cell

TYPE 2 DM

FFA TNF-a, resistin

IL-6, IL-18, PAI-1

adiponectin

Dysfunctional adipocyte – the best friend of a cancer cell

Zhang, Scherer PE, 2018

Metabolic dysfunction, inflammation

The tissue / cellular / molecular mechanisms behind

the negative impact of obesity on health:

• Lipotoxicity

• Chronic inflammation

• Hypoxia

• Mitochondrial dysfunction / reduced oxidative capacity

• Insulin resistance

• ...

Adipose tissue dysfunction:

• increased fat cell size / reduced differentiation capacity

• insulin resistance - increased lipolysis & release of fatty acids

• shift in adipokine profile – chronic inflammation

• mitochondrial dysfunction

InzulínováRezistencia

Prediabetes

Obesity

DyslipidemiaHypertension

Metabolic syndrom

Low physical

fitness

Low

adiponectinInflammation

Hyperuricemia

Low physical

fitness

Steatosis

METABOLIC

SYNDROM

VISCERAL

OBESITY

DYSLIPIDEMIAGLUCOSE

METABOLISM

HYPERTESION

Type 2 DIABETES

CARDIOVASCULARE

DISEASE

ONCOLOGIC

DISEASES

NEURODEGENERATIVE

DISEASE(Alzheimerova & Parkinsonova ch)

LOW

PHYSICAL

FITNESS

Metabolic syndrom:Integrated pathophysiology of chronic diseases

Hassinen et al, 2008

SARCOPENIA

Sarcopenia: a loss of muscle mass and strength, linked to ageing,

physical inactivity and chronic diseases

40 yrs

trained

74 yrs

sedentary

74 yrs

trained

https://bodyagefitness.files.wordpress.com/2014/08/muscle-mass-loss.png

Young man Senior

Skeletal muscle mass is comparable

in 40-year old and 74-year old athlet

Diagnosis of obesity

• BMI (body mass index) =

• Body composition

(bioelectric impedance, MRI, CT, DEXA)

Percentage of body fat

underweight < 19

normal weigh 19 - 24,9

overweight 25 - 29,9

obesity > 30

weight (kg)

height (m) 2

men > 25 %

women > 30 %

Grade I Obesity: BMI 30-34,9 kg/m2

Therapy lifestyle, pharmacoth

Grade II obesity: BMI 35-39,9 kg/m2

Lifestyle, pharmacoth, bariatric surgery

(only if comorbidity is present)

Grade III obesity: BMI >40 kg/m2

Lifestyle, pharmacoth, bariatric

surgery

• Waist circumference

• WHR (waist-hip ratio) =

• caliper

waist

hip

men > 0,9

women > 0,8

Diagnosis of obesity

men > 94 cm

women > 80 cm

(http://spittoon.23andme.com/2009/06/18/researchers-look-to-the-future-of-obesity-genetics/)

men > 102 cm

women > 88 cm

European criteria American criteria

Diagnosis of obesity

• Family history, risk factors, drugs

• Weight, height, BMI, waist circumference

• Bioimpedance – body composition

• Food intake profiling (questionnaires)

• Physical activity profiling (questionnaires, accelerometers,

indirect calorimetry, sporttesters)

• Physical fitness (VO2max)

• Laboratory tests (glycemia, lipid profile, endocrine profile...)

• Comorbidities

Obesity-associated comorbidities

• Metabolic complications: Metabolic Syndrom, type 2 diabetes

• Endocrine disorders: hyperestrogenism, hyperadrogenism in females,

hypogonadism, hypercortisolism, GHD, lower sympatoadrenal activity

• CVD (hypertension, cardial hypertrophy, IHD, arhytmias, sudden cardiac

death, tromboembolism, stroke)

• Respiratory complications (asthma, OSA sy, Pickwick sy)

• GIT (GE reflux, hernias, steatosis, pancreatitis, cholelithiasis... )

• Gynecology (infertility, amenorea..., complications during pregnancy and

delivery...)

• Oncology (ca: endometrium, breast, ovaries... GIT – colorectal, liver,

pancreas, gall bladder, urological – prostate and kidneys)

• Orthopedic (degeneration of joints, osteoarthritis....)

• Psychological complications: discrimination, low self esteem, low

motivation, depression, anxiety

• Others: skin, edema, infections, impaired wound healing....

Years of life lostthe impact of health consequencies of obesity

• Obese men live cca 5,8 years shorter life expectancy

• Obese women 7,1 shorter life expectancy

(Framingham’s study)

• Greater impact of visceral obesity on mortality risk –

20-30% increase

“Morbid obesity” (grade III obesity)

BMI>40 kg/m2

Bariatric surgery,

aimed at achieving

sustainable weight loss

Indications: BMI>40 kg/m2

BMI>35 kg/m2 + T2D,

MS…

Effects:

• decrease of fat mass

• decrease of blood lipids

• decrease of blood pressure

• decrease of blood glucose

• improvement of insulin sensitivity

• Lifestyle intervention

(diet and exercise)

• Pharmacological

- orlistat – decreases the absorption of lipids (decreases the

activity of pancreatic lipase)

- rimonabant – decreases apetite and food intake (antagonist

of CB1 receptor)

- sibutramine – decreases food intake (inhibits „re-uptake“ of

serotonine, noradrenaline and dopamine)

- Mysimba

- Future: combined “tailored” therapy (amylin, leptin, CCK)

- “exercise in a pill”, “caloric restriction in a pill”

Therapy of obesity

Bariatric surgery

Gastric banding is not

being used anymore

Effect of bariatric surgery on health

• Weight loss and adipose tissue loss, adipose tissue redistribution

• Improved insulin sensitivity

• Improved B cell function

• Improvement of CVD risk factors

• Improvement of non-alcoholic steatosis

Effects of physical (in)activity:

Exercise is medicine

„Fit & fat“ OR „unfit & unfat“ ? Health benefits of regular exercise independent from weight reduction

Metaanalysis aimed at the joint association of aerobic fitness and weight status on

all cause mortality. 10 prospective studies, objectively measured fitness and BMI.

Compared to normal weight-fit individuals:

- unfit individuals had 2x increase in the risk of mortality regardless of BMI;

- overweight & obese-fit individuals had similar mortality risks as

normal weight-fit individuals.

Physical activity-based interventions as a part of complex lifestyle modification

rather than purely weight-loss driven approaches to reduce mortality risk.

(Barry, Blair et al., 2014)

Sui, Blair, JAMADeath rate

Fit

Unfit

• reduced risk of CVD, metabolic,

neurodegenerative, oncologic

diseases

• improved lipid profile

• improved blood pressure

• better compensation of diabetes

• prevention of osteoporosis

• reduction of inflammation

Benefits of regular physical activity

• optimal body weight

• improved immune functions

• better stress management, mood improvement

Diseasome of physical inactivity

Pedersen BK, 2010

~30% of population in

Slovakia has a

recommended dose

of physical activity Jurkovičová, 2005

Neurodegenerativ

e diseasesType 2

diabetes

Two weeks of physical inactivity decreased

insulin sensitivity in young healthy adults

Krogh-Madsen R et al. J Appl Physiol 2010;108:1034-1040

• lower fitness

(VO2max -7%)

• reduced muscle mass and

strength

• increased visceral fat (7%)

8 days of inactivity: a loss of

~1,2 kg muscle mass

Reduction of type 2 diabetes risk in prediabeticsDiabetes Prevention Program

58%

31%

0

20

40

60

80

100

Ris

kre

duction

(%)

Exercise with medium

intensity, 150 min/week, low caloric, low fat diet

Lifestyle Intervention Metformin

DPP Research Group. NEJM 2002; 346:393-403

DPP Research Group, 2015 Lancet

The impact of long-term lifestyle modification on

the incidence of T2D: Diabetes Prevention Program & Da Qing

study:3-6 years follow-up: 50-60% reduction in progression to type 2 diabetes

Cu

mu

lative

in

cid

en

ce o

f T

2D

Li et al, 2008 Lancet

Physical fitness: ability to produce acceptable physical

performance, associated with activity in specific environment

Biological parameters of physical fitness1. Morphology / anthropometry 4. Motoric parameters

• Height and body weight

• Body composition

• Subcutaneous fat distribution

• Visceral fat content

• Bone density

• Agility

• Balance

• Coordination

• Speed

• Flexibility

2. Cardiorespiratory parameters 5. Metabolic parameters

• Submaximal capacity to exercise

• Maximal aerobic capacity

• Cardial functions

• Pulmonary functions

• Blood pressure

• Glucose tolerance

• Insulin sensitivity

• Inflammatory markers

• lipid a lipoprotein metabolism

• Metabolic substrate preference

3. Muscular parameters 6. Molecular parameters ???

• Strength

• Endurance

• Dynamics of muscle contraction

• Power

Different parameters of physical fitness are

used for diagnostics and individualized

training intervention design and effectivity

assessment .

Everyday physical activity and BMI

% pohybovej aktivity s intenzitou >3 METs

20

25

30

35

40

BM

I (k

g/m

2)

0 10 20 30 40 50 60 70

R=-0,39

p<0.0003

N=85

štíhli

obézni

prediabetes

T2DM

20

25

30

35

40

BM

I (k

g/m

2)

100 300 500 700 900 1100 1300

Počet krokov za 1 hodinu

R=-0,36

p<0.0008

N=85

Volume and dynamics of physical activity is associated with obesity and

metabolic disease in 85 middle-aged men.Pohybová aktivita bola monitorovaná počas celého dňa pomocou akcelerometrov. % pohybovej

aktivity s intenzitou >3 MET predstavuje proporciu dynamickej aktivity s energetickým výdajom

presahujúcim 3-násobok pokojového výdaja energie; MET - metabolický ekvivalent (Ukropcová, Sedliak, Ukropec, Via practica 2015)

Mechanisms of exercise-induced health

benefits

Reduction• Visceral/ectopic adipose tissue

• Lipotoxicity

• Chronic systemic subclinical

inflammation

• Oxidative stress

Improvement of

• Biological effect of insulin & other

hormones (incretins, IL6 in muscle,

adiponectin, leptin..)

• Metabolic & secretory profile and

differentiation capacity of adipose

tissue

Induction of

• Synthesis and secretion of

protective myokines/exerkines

• Mitochondrial biogenesis and

function

• Skeletal muscle volume and

strength, physical fitness

Ross a spol. J Appl Physiol (1996)

Hunter a spol. Med Sci Sports Ex (2002)

Eves, N.D. a Plotnikoff, R.C. Diabetes Care (2006)

Hills, A.P., a spol. Obes Rev (2010)

Liu-Ambrose, T., a spol. Arch Intern Med (2010)

Kirk-Sanchez a McGough, Clin Interv Aging (2014)

Pedersen, B.K. J Physiol (2009)

Fiuza-Luces C et al,

2013

Effects of 3-month training on abdominal

adiposity

There was an evident decrease in visceral adiposity in

middle aged men (A,B,C,D) in response to a 3-month

training(Ukropcová a spol, Klinická obezitológia, 2013)

Effect of 3-month training on hepatic lipid

content (1H-MRS)

An extreme case of

lipid deposition in

liver(A)

In association with visceral

adiposity (B).

Effect of 3-month

training on lipid content

in liver (C)

There was a 10% decrease

in liver fat following 3-month

training in men(Ukropcová, Ukropec, Klinická

obezitológia, Krahulec a spol 2013).

Physical activity in prevention

& treatment of obesity

• The role for physical activity in body weight regulation is

controversial. Regular exercise reduces fat mass and

abdominal obesity and prevents sarcopenia typically

associated with diet-induced weight loss.

• Physical activity is essential for body weight maintenance,

especially following weight loss.

• 45-60 minutes of medium intensity PA (40-59% HR max)

per day is a good prevention of body weight gain.

• At least 60-90 min of medium intensity PA / day might be

necessary for the long term body weight reduction

maintenance.

Exercise to induce body weight reduction(FITT: frequency, intensity, time, type)

• Frequency: ≥ 5 days per week

• Intensity: medium or high intensity (40-60% HRmax with

progression towards 50-75% HRmax)

• Duration: 30-60 min/day, in total 150 min/week

with progression towards ≥ 300 min/week

• Alternatives for continuous exercise: intermitent

exercise with accumulation of several at least 10-min

lasting exercise sessions

• Type of exercise: primarily aerobic exercise but also

resistance exercise using large muscle groups

(≥2x/week)

Intensity of Physical Activity

low intensity medium

intensity

high intensity very high

intensity

< 40% of HRM 40-59% of HRM 60-80% of HRM 80-100% of

HRMTo compare energy demands for distinct types of physical activity: metabolic equivalent - MET. MET expresses activity-related energy demands as a multiple of the Resting Energy Expenditure.

MET multiples express the level of Physical Activity Intensity> 3 MET - low intensity3-6 MET – medium intensity 6-8 MET - high intensity ➢8 MET - very high intensity

(Ukropcová , Ukropec, In. Klinická obezitológia, Krahulec a spol 2013)

Strength exercise for overweight to obese patientsACSM recommendations

• frequency: 2-3x/week

• duration of the training unit: not more than 1 hour (8-10

units)

• type of exercise: big muscle groups

(back and abdominal skeletal muscles, extremities),

1-2 series per muscle group (8-12 repeats), a break

between the series 2-3min

• intensity: 60% - 80% 1RM

48 hours break necessary between two strength training

sessions!

Strength training is supplementary to aerobic training, with the

aim to increase muscle mass and strength and REE; should

be supervised.

Gradual adaptation to physical activity is

inevitable protection against side effects

• The most frequent complication in obese: injuries – obese

individuals have 7% more injuries compared to lean. Acute

physical activity increases the risk of injury in obese

inactive individuals by 26%.

• Sudden cardiac death, associated with exercise, is very

rare (0-2 / 100 000 h of intense physical activity).

Higher fitness levels reduce the risk of exercise-

induced injuries / complications

Physical activity, obesity and comorbidities

• Regular aerobic physical activity is the most

effective nonpharmacological means of improving

endothelial function. A better functional state of

endothelium represents one of the best cardioprotective

mechanisms of regular physical activity.

• Regular physical activity and fitness have

antiinflammatory effect in obese individuals.

• Studies have shown 30-40% risk reduction of

colorectal ca in physically active men and women.

The effect of PA is independent of BMI. ~30-60 min of

medium to high intensity physical activity per day is

necessary for a risk reduction.

Physical activity in treatment of obese T2D

• improves metabolic compensation and cardiovascularrisk factors (reduced blood pressure, improved lipid profile, improved endothelial function) as well as physical fitness

• Regular physical activity reduces glycemia and insulinemia, improves insulin sensitivity, reduces subclinicalinflammation and positively modifies body composition, independent from weight loss

• Increases muscle strength and flexibility, REE and quolityof life

• „LookAhead“ study – reduction of glycemia and HbA1c, reduction of body weight (-8,6%) and increased physical fitness (+21%) in T2D in lifestyle modification program.

Long term health benefits and obesity management requires

complex multidisciplinary approach,

based on a team of experts in the field of obesity:

(i) physicians

(ii) nutrition specialist

(iii) physiotherapist

(iv) psychologist

- Education (patients, health personel, medical students)

- Networking (physicians, specialists)

- Research with translation to clinical practice

Centers of Obesity Management, COM:

complex solution to a complex problem

„A man can run longer than most animals,

also thanks to the long legs, big gluts and

the ability to get rid of heat.“

prof. Daniel Lieberman

Thank you.

If you have any question,

please write to:

barbara.ukropcova@gmail.com