Obesity Pathophysiology and Genetics Flashcards by Brian McDaniel

Effects of the sympathetic nervous system on obesity

Increased brown fat thermogenesis

Increased adipose lipolysis

Increased spontaneous locomotor activity and myocardial activity

Increased muscle glycogenolysis, glucose, and fatty acid oxidation, and protein synthesis

Overall increased energy expenditure and decreased food intake

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Is Serotonin orexigenic or anorexigenic

Anorexigenic, suppresses food intake

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Where is POMC created

Arcuate Nucleus

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Bardet-Biedl Syndrome is inherited via this type of inheritance

Autosomal recessive inheritance

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Stress is particularly linked to this type of obesity

Visceral adiposity

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The circadian rhythm is primarily regulated by this part of the brain

SCN Suprachiasmatic Nuclei (anterior hypothalamus)

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Obesity is correlated with these changes in gut microbiota

Obesity causes a decrease in gut bacteroidetes and increased firmicutes

Bacteroidetes:Firmicutes ratio is low

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Ghrelin is suppressed most by intake of this type macronutrient

Protein

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This part of the brain is involved with impulse control and decision making

Prefrontal cortex

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This type of obesity causes red hair, pale skin, hypopigmentation, low blood pressure, corticosteroid deficiency and adrenal insufficiency (low ACTH)

POMC Mutation

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Which hormones are increased by Bariatric surgery

Adiponectin
CCK
GLP-1
PYY
Glucagon

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What type of obesity presents with developmental delay, short stature, short fingers, hypocalcemia, pseudohypoparathyroidism, precocious puberty, mild cognitive defects, and round facies

Albright Hereditary Osteodystrophy

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What is CCK

Cholecystokinin

Short term satiation leading to meal termination

Slows gastric emptying

Stimulates pancreatic enzymes and bile

Opposes grehlin

Stimulated by fat and protein intake

Released by the I cells primarily in the duodenum

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Is POMC orexigenic or anorexigenic

Anorexigenic, decreases food intake

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What is Leptin?

An adipokine (created in fat) that acts in the hypothalamus (primarily Ventromedial hypothalmus)

Is increased in obesity/overfed –> General obesity is associated with Leptin resistance

However lack of Leptin leads to obesity also

Decreased appetite and increases energy expenditure.

Levels drops quickly when start to calorie restriction or have bariatric surgery

Along with Insulin, cross talks between homeostatic and hedonic system

Along with insulin activated the Sympathetic system (POMC/CART…)

Decreases as insulin decreases

Can be effected by poor quality sleep and fasting.

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What activates AgRH/NPY

Ghrelin

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Thiazolidinediones increase this obesity related hormone

Adiponectin

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Hypoperfusion of the right frontal lobe leads to this change in weight

Overeating and Klein-Levin Syndrome

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The prevalence of mono genetic obesity syndromes is higher in what area of the world

Eastern world (Pakistan, Turkey, Egypt, Austria …)

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Gourmand Syndrome involves damage to this part of the brain

Right frontal lobe injury

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Change in level of Leptin and Insulin in overfed state

Increased

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GLP-1 is secreted by

I cells of the pancrease

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What testing is done to eval for Bardet-Biedl Syndrome

Molecular testing for the BBS gene locus mutation

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Glucagon is secreted from

alpha cells of pancreas

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This type of obesity is caused by a maternal epigenetic methylation defect in adenylate cyclase-stimulating G alpha protein

Albright Hereditary Osteodystrophy

Melanin Concentrating Hormone is created here

Lateral Hypothalamus

Difference between hunger and appetite

Hunger is physical need for food Appetite is a desire for food that can be emotional, sight/smell based etc

Change in level of GLP-1 after bariatric surgery

Increased

Where is serotonin created

Raphe nuclei in the brainstem

This part of the hypothalamus is the “satiety center”. Lesion in this area in mice causes obesity

Ventromedial hypothalamus (VMH) Dense in Leptin receptors Produces brain-derived neurotrophic factor (BDNF)

Does POMC/CART/MCR ultimately leads to activation of the sympathetic or parasympathetic system?

Sympathetic

Difference between probiotics and prebiotics

Prebiotics are non-digestible polysaccharides Probiotics are live microorganisms

What is an adipokine? Most important examples

Cell signaling proteins/cytokines secreted by adipose tissue Leptin Adiponectin

Compared to lean individuals, in obese individuals Glucagon levels are

High

This part of the hypothalamus is the “hunger center”. Lesion in this area in mice causes anorexia

Lateral Hypothalamus (LH) Creates melanin concentrating hormone (MCH)

What is adiponectin

An adipokine that is low in obesity and increases after bariatric surgery Insulin sensitizing in the muscle. Anti-atherosclerosis effect. Increases fatty acid oxidation Increased by TZDs

In mice models, when exposed to light at night what happens

Shift timing of food intake Overall calorie intake doesn’t change, but does correlate with obesity

Change in Leptin and Insulin levels after bariatric surgery

Decreased

What type of obesity presents with hypotonia, blindness, polydactyly, hypogonadism, and retinitis pigmentosa

Bardet-Biedl Syndrome

Does AgRP/NPY ultimately leads to activation of the sympathetic or parasympathetic system?

Parasympathetic

What testing is done to eval for Prader Wili

DNA Methylation analysis

What is correlated with increased brown fat thermogenesis

``` Cold Thermic effect of food Women have more then men Young have more than old Lean have more than obese ``` Especially high in newborns and hibernating animals Sympathetic nervous system innervation

The most common known genetic cause of obesity

Melanocortin 4 Receptor Deficiency

The only circulating orexigen is

Ghrelin

Which hormones are high in obesity

Leptin Insulin Glucagon Ghrelin high in PWS. Unclear if high in general obesity

Change in level of Amylin in overfed state

Increased

Site of action of insulin

Hypothalamus

Effects of Alpha Melanocyte Stimulating Hormone on appetite

Decreased

What parts of the brain are involved with the Hedonic Pathway

Ventral Tegmental Area Nucleus Accumbens Frontal Accumbens

Which hormones are decreased by Bariatric surgery

Leptin Ghrelin Insulin

How is stress linked to obesity

Like transient diabetes Stress —> Cortisol —> insulin resistance —> Leptin resistance

Dementia with degeneration of the right frontal lobe leads to this change in weight

Hyperphagia and weight gain

What inhibits AgRH/NPY

POMC

This type of obesity presents with tall stature, normal mental status, increased lean muscle mass and hyperphagia

Heterozygous MC4R frameshift mutation

Compared to lean individuals, in obese individuals Leptin and Insulin levels are

High

Leptin is created here

White fat

This type of syndromic obesity can be very successfully treated

Leptin deficiency, treat with Leptin There is a new drug Setmelanotide that shows promise in POMC deficiency

Change in level of CCK after bariatric surgery

Increased

What activates Cocaine and Amphetamine Regulation Transcript (CART)

Insulin and Leptin

Which hormones are decreased in an over fed state and increased in an underfed state

Ghrelin

CCK is secreted from

I cells in the duodenum

This type of genetic obesity has increased Ghrelin

Prader Willi Syndrome

Change in level of Adiponecton after bariatric surgery

Increased

This type of obesity is caused by a autosomal recessive defect in cilia

Bardet-Biedl Syndrome

Does Insulin ultimately leads to activation of the sympathetic or parasympathetic system?

Sympathetic

What is PYY

Increases satiety and stimulates glucose mediated insulin secretion. Degraded by DPP-4 Secreted by intestinal I cell (most in the ileum/colon) Experimental drug combo used for obesity

This system in the nervous system is implicated in desire for food palatability and reward seeking behavior

Hedonic System

Prader Wili has what changes in Leptin and Grehlin

Increased ghrelin Leptin increased, but at similar level to non-syndrome obese

Change in level of Ghrelin in overfed state

Decreased

Compared to lean individuals, in obese individuals GLP-1 levels are

Low

What 2 substances are secreted by the pancrease to decrease hunger and increase satiety

Amylin | Insulin

What is an Orexigen

Hormone or substance that stimulates appetite

What activates POMC

Leptin Insulin Through LepR

Change in level of Glucagon in overfed state

Increased

How does the activity of the dorsolateral prefrontal cortex in obese patients compare to lean patients

Decreased activation potentially causing less impulse control Remains low even after weight loss Is increased in obese children and is linked to low self esteem

This obesity condition includes short stature, hypotonia and developmental delay as well as narrow temple distance, narrow nasal bridge, almond shaped eyes, mild strabismus, and downturned upper lip

Prader Willi

Change in level of PYY in overfed state

Increased

Appetite from the hedonic system is highest when _ is low

Insulin and Leptin

Which type of adipose tissue is more dangerous

Visceral adipose (in liver, pericardium, muscle etc) Subcutaneous fat is much less dangerous

This part of the brain creates brain-derived neurotrophic factor (BDNF) which is involved in hedonic and homeostatic energy regulation and if decreased can contribute to obesity

Ventromedial hypothalamus

What inhibits POMC

AgRH | NPY

What is Ghrelin

Growth Hormone Release Inducing Peptide Hunger hormone, peaks before meals Secreted by the fundas Suppressed the most by protein intake Increased in Prader Wili Increase when calorie restrict

What is GLP-1

Secreted by I cells in the intestine (the most in ileum/colon) Degraded by DPP-4 Increases beta cell insulin release, delays gastric motility/secretions, delays carb absorption, and increases satiety (by inhibiting orexigenic NPY)

What type of obesity presents with altered immune system, delayed puberty, and hyperphagia

Congenital Leptin Deficiency | Congenital Leptin Receptor Deficiency

This neurotransmitter stimulates MCR4 and inhibits AgRP/NPY

Proopiomelanocortin (POMC)

This type of obesity has very high levels of Leptin

Leptin receptor deficiency

Change in level of GLP-1 in overfed state

Increased

Is Agouti Related Peptide (AgRP) orexigenic or anorexigenic

Orexigenic, increases food intake

Where is AgRP created

Arcuate Nucleus

What 3 substances are secreted by the intestine to act peripherally decreasing hunger and increase satiety

CCK GLP-1 PYY

This general picture should raise concern for genetic obesity

Normal birth weight followed by rapid severe onset of obesity with impaired satiety, hyperphasia, and constant food seeking behavior

This virus has been linked to an infectious type of obesity

Adenovirus 36 30% in obese humans and 11% in thin Presence of antibodies among population has been increasing Induced obesity in animal models Thought to induce stem cell differentiation into preadipocytes via PPAR gamma signaling

These hormones from the homeostatic system augment the affects of the hedonic system

Insulin/Leptin cross talk to hedonic dopamine system by affecting dopamine’s reuptake and clearance from the synapse

Is Neuropeptide Y (NPY) orexigenic or anorexigenic

Orexigenic, increases food intake

Concentration of Dopamine receptors in the brain of obese people compared to lean

Less Unsure if cause or affect

This is the signature protein in brown adipose tissue thermogenesis

Uncoupling protein 1 (UCP1) which uncoupled oxidative phosphorylation in mitochondria generating heat

Patient with frontal lobotomy’s have this effect on weight

Overeating and obesity

Change in level of PYY after bariatric surgery

Increased

Which hormones are low in obesity

Adiponectin CCK GLP-1 PYY

What neurotransmitters does the Arcuate nucleus create

POMC NPY AgRP

Compared to lean individuals, in obese individuals Adiponecton levels are

Low

Leptin acts here

Hypothalamus (Ventromedial hypothalmus)

PYY is secreted from

I cells in the duodenum

Change in level of CCK in overfed state

Increased

This part of the brain is most closely associated with Norepinephrine production

Locus Coeruleus

Which hormones are increased in an over fed state and decreased in an underfed state

``` Leptin CCK GLP-1 PYY Amylin Insulin Glucagon ```

What is Leptin?

An adipokine (created in fat) that acts in the hypothalamus (primarily Ventromedial hypothalmus) Is increased in obesity/overfed --> General obesity is associated with Leptin resistance However lack of Leptin leads to obesity also Increases appetite and decreases energy expenditure. Levels drops quickly when start to calorie restriction or have bariatric surgery Along with Insulin, cross talks between homeostatic and hedonic system Along with insulin activated the Sympathetic system (POMC/CART...) Decreases as insulin decreases Can be effected by poor quality sleep and fasting.

Changes in adiponectin are associated with what health conditions (independent of obesity)

Low in T2DM, NASH, atherosclerosis, MI, and CHF High in osteoarthritis

This adipokine is increased in obese and leads to atherosclerosis and insulin resistance

Resistin

Effect of insulin on appetite

Decreases food intake

Compared to lean individuals, in obese individuals PYY levels are

Low

This is the "anti-Ghrelin" which leads to short term satiation and meal termination

CCK

What is Amylin

Decreases food intake, inhibits gastric emptying, inhibits gastric acid secretion, enhances CCK, and effects bone metabolism Consecreted with insulin by pancreatic beta cells Symlin/Pramlintide is a diabetic drug being studied for possible use in combo weight loss medications

Where is NPY created

Arcuate Nucleus

Compared to lean individuals, in obese individuals CCK levels are

Low

This type of obesity is caused by a epigenetic 15q partial deletion on paternal chromosome

Prader Willi

Anorexigens

Hormone or substance which inhibits hunger and promotes satiety

This type of obesity has very low levels of Leptin

Leptin deficiency

Most abundant adipokine

Adiponectin

Does Grehlin ultimately leads to activation of the sympathetic or parasympathetic system?

Parasympathetic

When bacteria free mice are given a microbiota transfer of obese vs lean donor, what happens

Mouse adopts phenotype of donor

Klein-Levin Syndrome is caused by this

Hypoperfusion of the right frontal lobe

Hyperactivity of the right prefrontal cortex leads to this change in weight

Anorexia and weight loss

The primary neurotransmitter of the Hedonic Pathway is

Dopamine

Ghrelin is secreted by

Fundas of the stomach

Does Leptin ultimately lead to activation of the sympathetic or parasympathetic system

Sympathetic