Obesity Pathophysiology and Genetics Flashcards
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
Is Serotonin orexigenic or anorexigenic
Anorexigenic, suppresses food intake
Where is POMC created
Arcuate Nucleus
Bardet-Biedl Syndrome is inherited via this type of inheritance
Autosomal recessive inheritance
Stress is particularly linked to this type of obesity
Visceral adiposity
The circadian rhythm is primarily regulated by this part of the brain
SCN Suprachiasmatic Nuclei (anterior hypothalamus)
Obesity is correlated with these changes in gut microbiota
Obesity causes a decrease in gut bacteroidetes and increased firmicutes
Bacteroidetes:Firmicutes ratio is low
Ghrelin is suppressed most by intake of this type macronutrient
Protein
This part of the brain is involved with impulse control and decision making
Prefrontal cortex
This type of obesity causes red hair, pale skin, hypopigmentation, low blood pressure, corticosteroid deficiency and adrenal insufficiency (low ACTH)
POMC Mutation
Which hormones are increased by Bariatric surgery
Adiponectin CCK GLP-1 PYY Glucagon
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
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
Is POMC orexigenic or anorexigenic
Anorexigenic, decreases food intake
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.
What activates AgRH/NPY
Ghrelin
Thiazolidinediones increase this obesity related hormone
Adiponectin
Hypoperfusion of the right frontal lobe leads to this change in weight
Overeating and Klein-Levin Syndrome
The prevalence of mono genetic obesity syndromes is higher in what area of the world
Eastern world (Pakistan, Turkey, Egypt, Austria …)
Gourmand Syndrome involves damage to this part of the brain
Right frontal lobe injury
Change in level of Leptin and Insulin in overfed state
Increased
GLP-1 is secreted by
I cells of the pancrease
What testing is done to eval for Bardet-Biedl Syndrome
Molecular testing for the BBS gene locus mutation
Glucagon is secreted from
alpha cells of pancreas
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
