Obesity… What do hormones have to do with it? Hala Mosli PGY4 June 10 th, 2009.

Obesity…Obesity…What do hormones have to What do hormones have to

do with it?do with it?Hala Mosli

PGY4

June 10th, 2009

Objectives

-A look back at obesity

-Definition of obesity

-Pathophysiology

-Hormones and obesity

-Effect of obesity on other hormonal systems

-Effect of bariatric surgery

• Obesity is from the Latin obesitas, which means "stout, fat, or plump." Ēsus is the past participle of edere (to eat), with ob (over) added to it.

• The Oxford English Dictionary documents its first usage in 1611 by Randle Cotgrave in A Dictionarie of the French and English Tongues

• There were times that obesity was viewed as a measure of wealth and affluence, or as an inevitable result of them.

• Throughout history, Man’s size changed drastically, as did his views on obesity.

“There are those beings who have vowed not to enter Nirvana until they have helped all others realize enlightenment. Hotei is this kind of Bodhisattva. He is one of the Shichi Fukujin, the Seven Japanese Shinto-Gods of Luck. His fat stomach, which protrudes from the robes he wears, symbolizes the largeness of his soul. It is also a symbol of happiness, luck, and generosity. His large elongated earlobes are a sign of wisdom. Hotei was a wandering monk who goes around and takes the sadness from the people of this world. Just his appearance has the ability to cheer anyone up from a bad day. His largely exposed, pot-belly stomach protrudes in front of him as he continues to laugh through never-ending-time. He is admired for his happiness, plenitude, contentment and his loving and cheerful character...“

• Obese females were thought to depict fertility during certain era, and in many religious beliefs.

But…

• Hippocrates states that "Corpulence is not only a disease itself, but the harbinger of others".

• Physicians throughout history made the connection between being overweight and many illnesses.

• And as man evolved, slimness became the measure of wealth, affluence and sophistication.

Definition

• Based on Body Mass Index (BMI)

• BMI=wt(kg)/ht(m)2

• Large epidemiological studies have established an inverse relationship between BMI>25kg/m2 and mortality.

What makes people obese?• Intake>output.

• Genetics play an important role.

• Monogenic causes have been identified:• Leptin gene mutation• Leptin receptor mutation• Prohormone Convertase 1 gene mutation• POMC gene mutation• Melanocortin 4 receptor mutation• TrkB

• Obesity associated with pleiotropic syndromes.

• Obesity syndromes due to chromosomal rearrangements:

• Prader-Willi Syndrome• SIM1 Gene mutation

• Polygenic causes of obesity• More than 600 genes and chromosomal regions• www.obesitygene.pbrc.edu• Major challenges remain.

• Obesity associated with pleiotropic syndromes.

• Obesity syndromes due to chromosomal rearrangements:

• Prader-Willi Syndrome• SIM1 Gene mutation

• Polygenic causes of obesity• More than 600 genes and chromosomal regions• www.obesitygene.pbrc.edu• Major challenges remain.

What is “fat”?

• TGs stored within adipose tissue are the body’s major energy reserve.

• TGs account for 85% for the adipocyte’s weight.

• Lean persons die after ~ days of starvation

• Obese persons have tolerated therapeutic fasts for over 1 YEAR without adverse effects

• The role of the hypothalamus-pituitary axis initially suggested by Fröhlich at the end of the nineteenth century.

• The most definitive evidence of the vital role of the hypothalamus was provided by Hetherington and Ranson who demonstrated that destruction of the medial basal hypothalamus could result in neuroendocrine derangements and morbid obesity.

• Ghrelin: • Motilin-related peptide.• Expressed by the gastric mucosa.• Also produced in the arcuate nucleus of the hypothalamus,

where it stimulates release of GH from the ant. Pituitary.• 28-AA GH releasing factor via GHS-R• Role in appetite regulation…stimulates hunger.• Regulation of insulin sensitivity and hepatic glucose output.• Other roles.• Concentration of ghrelin differs between the sexes; it is

higher in females in the follicular stage than in males.• Ghrelin was found to be one of the most powerful orixogenic

and adipogenic agents known in mammalian physiology.• High preprandial ghrelin:obestatin ratio is thought to play a

role in the pathophysiology of obesity.

• Obestatin:• A peptide derived from the ghrelin precursor.• A novel hormone whose peripheral

administration or delivery into the lateral brain ventricle originally appeared to decrease food intake, body weight gain and GI function, i.e. functionally opposite effects to those of ghrelin.

• These findings have repeatedly been questioned by later studies.

• Leptin:• Secreted by adipocytes into the bloodstream.• Has pleiotropic effects on food intake,

hypothalamic neuroendocrine regulation, reproductive function and energy expenditure.

• Levels decrease rapidly within 12 hours of onset of starvation.

• Levels increase in response to overfeeding.• Plasma leptin concentration and BMI are directly

related.

• Resistin:• Secreted by adipose tissue.• Signaling polypeptide.• Proposed hormone that links obesity to diabetes.• Mainly studied in mice!

• Adiponectin:• Most abundant secretory protein produced by

adipocytes.• Plasma concentrations are decreased in obesity

and insulin resistance, improve with interventions that increase insulin sensitivity.

• Suggestion that decreased adiponectin contribute to some of the metabolic complications associated with obesity.

• Visfatin:• Newly isolated adipocytokine.• Expression increases with the level of obesity.• Behaves like insulin; binds to the same receptor

and exerts similar activity but through a different mechanism.

• Plasma concentrations are much lower than those of insulin (10%).

• Estrogens:• Adipose tissue has P450 aromatase activity.

• Estrone is the second major circulating estrogen in premenopausal women and the main estrogen in postmenopausal women.

• Higher in lower body obesity than in upper body obesity.• May have a role in autocrine and paracrine action.

• IL-6:• Adipose tissue IL-6 secretion might account for

30% of circulating IL-6• Obesity is associated with increased IL-6

systemic inflammation and insulin resistance.• Insulin sensitivity is inversely related to IL-6

concentrations. IL-6 directly impairs insulin signalling.

• Exogenous IL-6 induces elevated FBG.

• TNF-α:• Secreted by adipocytes.• Expression is increased in the enlarged adipocyte

of an obese person.• Likely has paracrine rather than endocrine effect.• The effects include impaired insulin signalling.• Proposed role in insulin resistance in obesity.

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Obesity Disease BurdenObesity Disease Burden Diabetes Mellitus Type II (90 %) Cardiovascular (33 %)

Hypertension (62 %) Coronary Artery Disease Cardiomyopathy CHF (Bi-ventricular Dysfunction)

Pulmonary Hypertension Asthma Sleep Apnea (60 %) Stroke Gastroesophageal Reflux Gall Bladder (44%) and Liver Disease Behavior/Emotional Disturbances Impaired Quality of Life

Dyslipidemia/Elevated Cholesterol Renal Disease Urinary Incontinence Infertility/Menstrual Problems (50 %) Gout Cancer

Breast Endometrial Colon

Osteoarthritis (26 %) Low Back Pain Carpal Tunnel Complications of Pregnancy

Gallbladder Prostate Kidney

Premature Death (300,000 deaths /year)

The Effect of Bariatric Surgery on Resolution of Co-Morbidities and The Effect of Bariatric Surgery on Resolution of Co-Morbidities and Longevity, Arthur M. Carlin, Longevity, Arthur M. Carlin, MD, FACS,Director of Bariatric Research,Bariatric Surgery Center,Henry Ford Hospital, Detroit

How is all this affected by bariatric surgery?

Medical Co-Morbidities Resolved or Improved

Type 2 Diabetes 95%

Hypertension 92%

Cardiac Function 95%

improvement

Osteoarthritis 82%

Sleep Apnea 75%

GERD 98%

Stress Incontinence 87%

Hypercholesterolemia 97%

Wittgrove AC,Clark GW. Laparoscopic Gastric bypass roux-n-y-500 patients. Obese Surg 2000. And others.

SwedishSwedish Obesity Subjects (SOS)Obesity Subjects (SOS)

Sjostrom CD et al. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional

weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. 1999;4:477-484.weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. 1999;4:477-484.

Excluded from enteroinsular axis

Ghrelin??

↑ GLP-1

Undigested food

GIP??

Improved insulin sensitivity

↑ adiponectin

↓ leptin

Loss of fat mass

↓ CHO↓ calories

Mechanisms of DM resolution with GBP