KIN 404 1 Flashcards
What is diabetes mellitus?
A metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion, insulin action or both. The chronic hyperglycemia of diabetes is associated with significant long-term damage, dysfunction and failure of various organs – especially the kidneys, eyes, nerves, heart and blood vessels
Characeristics of type I diabetes
Absolute deficiency of insulin secretion due to autoimmuno destruction of beta-cells of the pancreas. Also called insulin-dependent diabetes/juvenile onset diabets. Account for only 5-10% of those with diabetes/
Characteristics of Type II diabetes
A combination of insulin resistance and relative insulin deficiency. Also called non-insulin-dependent diabetes/adult onset diabetes. No auto-immune destruction of beta-cells. Patients usually obese and particularly in the abdominal region
What is metabolic syndrome?
A clustering of chronic disease risk factors, including abdominal obesity, dyslipidemia (elevated TGs and/or low levels of HDL-C), elevated blood pressure and elevated fasting glucose
MetS is associated with substantially elevated risk of…
type 2 diabetes (5-fold) and of atherosclerotic cardiovascular disease (2-3 fold)
Neuronal population within the arcuate nucleus (ARC) of the hypothalamus that stimulate food intake?
Neurons that co-express neuropeptide Y (NPY) and agouti related peptide (AgRP) stimulate appetite
Neuronal population within the acruate nucleus (ARC) of the hypothalamus that suppress feeding?
Neurons co-expressing pro-opiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART) supress feeding
How do POMC neurons stimulate appetite?
alpha-melanocyte-stimulating hormone is produced and this binds to melanocortin-4 receptors in the paraventricular nucleus to suppress food intake
What is the orexigenic effect of NPY mediated by?
Stimulation of hypothalamic Y1R and Y5R in addition to local inhibition of POMC neurons in the ARC
In relation to food intake, what does BDNF do?
suppresses food intake
What is PYY, and what does it do?
Peptide tyrosine tyrosine (PYY)…acts in hypothalamus to decrease food intake. It also increases energy expenditure and delays gastric emptying in mice
What is PP, and what does it do?
Pancreatic Polypeptide…thought to reduce food intake directly through Y4R in the brainstem and hypothalamus
What is GLP-1, and what does it do?
Glucagon-like-peptide-1. …has a potent incretin effect, reduces food intake, supresses glucagon secretion and delays gastric emptying
What is GLP-2, and what does it do?
Glucagon-like-peptide-2…no effect on food intake, but stimulates crypt cell proliferation
What is oxyntomoduline, and what does it do?
Reduces food intake and increases energy expenditure
What is glucagon, and what does it do?
Produced by the alpha-cells of the pancreatic islets…reduces food intake and meal size in addition to reducing body weight gain
What is ghrelin, and what does it do?
It’s the only known orexigenic gut hormone…increases food intake and body weight with a reduction in fat utilization in rodents
What is CCK, and what does it do?
Cholecystokinin, first gut hormone shown to modualte food intake. May act to reduce food intake.
What is amylin, and what does it do?
Stored and released along with insulin in response to food intake. Reduces food intake and body weight and improves glycemic control and causes weight loss in patients with T2DM
What is leptin, and what does it do?
Adipokine that exerts its anorectic effect via the ARC. It inhibits NPY/AgRP neurons and activates POMC/CART neurons, resulting in reduced food intake and increased energy expenditure.
How does gastric bypass surgery affect ghrelin levels differently than diet induced weight loss?
Gastric bypass actually lowers ghrelin levels, whereas 24-hour diet induced weight loss actually increases ghrelin levels (making weight gain easier)
How does hypothalamic ciliary neurotrophic factor effect food intake?
Reduces AMPK signaling, and its effects are maintained in diet-induced obesity
A woman with a BMI of 24 would be classidied _______ and a man with a BMI of 29 would be ________
normal, overweight
An unnamed kin prof has undergone a # of tests in your clinic which have produced the following results: a fasting hyperinsulinemia in the highest quartile, normal blood glucose following an OGTT, BMI of 33, low fasting blood glucose, and high plasma TGs. What is your diagnosis?
Insulin resistance and obesity (not metabolic syndrome because he only has 1/4 risk factors, with elevated TGs to be the only risk factor)
Energy intake consists of?
Energy consumed and intake efficiency
Energy output consists of, the 2 main ones?
physical and resting metabolic rate (highest constituent)
What 2 streams of info are integrated to determine behavioural (feeding) and autonomic/endocrine responses?
Internal millieu (hormonal and neural) and environmental/lifestyle
What are the individual predispositions/”wiring” that influence both the cognitive and metabolic brain?
Genetics, epigenetics, imprinted, early life events
Adiposity signals are what type of satiation regulators?
Long term regulators
Hunger and satiety signals are what type of satiation regulators?
Hunger and satiety signals
Where is the appetite control center located?
In the hypothalamus and hindbrain (brain stem)
What do orixegenic/anabolic regulators of energy homeostasis do?
Signals that increase food intake and decrease energy expenditure through metabolic brain
What do anoregenic/catabolic regulators of energy homeostasis do?
Signals that decrease food intake and/or increae energy expenditure through metabolic brain
What is the ARC, and where is it located?
The arcuate nucleus located in the hypothalamus…contains both catabolic and anabolic first order neurons
What is the PVN and where is it located?
The paraventricular nucleus in the hypothalamus. ..contains second order catabolic neurons
What is the PFA/LHA, and where is it located?
Perifornical area/lateral hypothalamus in the hypothalamus…contain second-order anabolic neurons
What is the ME?
Median eminence…area in the hypothalamus where there is no blood brain barrier so that peripheral signals can enter and act on higher brain centres
What are NPY and AgRP?
Neuropeptide Y and Agouti Related Peptide…First order anabolic neurons located in the ARC that project onto anabolic neurons in the LHA
What is alpha-MSH?
First order catabolic neurons in the ARC that activate secondary neurons in the PVN
How are peptide hormones synthesized and stored?
Made in advance and stored in secretory vesicles
Compare and contrast Ghrelin and Obestatin?
Both hormones derive from the same precursor protein and are predominatly secreted by the stomach and released into the blood. However, each has a different receptor (GHS-R and GPR39 respectively) and has an opposite effect on food intake, body wegiht and GI motility. Obestatin is only biologicallt active when it is methylated, therefore, ghrelin is more biologically active
What is POMC?
Pro-opiomelanocortin is the precursor for alpha-melanocyte stimulating hormone (alpha-MSH) – a neuropeptide that suppresses appetite
Effect on food intake and energy expenditure of neuropeptide Y?
increases food intake and decreases energy expenditure…anabolic/orexigenic
Effect on food intake and energy expenditure of agouti-related protein?
increases food intake and decreases energy expenditure…anabolic/orexigeneic
Effect on food intake and energy expenditure of endocannabinoids?
increase food intake and decreaes energy expenditure…anabolic/orexigenic
Effect on food intake and energy expenditure of of melanin concentrating hormone?
increase food intake and decreases energy expenditure…anabolic/orexigenic
Effect on food intake and energy expenditure of of hypocretin/orexin
increases food intake and decreases energy expenditure
Effect on food intake and energy expenditure of cortiocptropin-releasing hormone
decreases food intake and increases energy expenditure…catabolic/anorexic
Effect on food intake and energy expenditure of cocaine amphetamine regulated transcript (CART)
decreases food intake and increases energy expenditure…catabolic/anorexic
Effect on food intake and energy expenditure of alpha-melanocyte stimulating hormone?
decreases food intake and increases energy expenditure…catabolic/anorexic
Effect on food intake and energy expenditure of gamma-aminobutyric acid (GABA)
increases food intake and decreases energy expenditure…anabolic/orexigenic
Effect on food intake and energy expenditure of serotin (5-HT)
Decreases food intake and increases energy expenditure…catabolic.anorexic
Increases in circulating ghrelin would result in: a) activation of anabolic neurons in ARC b) inhibition of catabolic neurons in ARC c) activation of orexigenic neurons in ARC d) a and b e) all of the above
e) all of the above
All of the following regarding leptin are true except: a) synthesized in ARC b) suppresses appetite c) inhibits orexigenic neurons in hypothalamus d) activates anorexigenic neurons in hypothalamus e) increases energy expendiure
a) synthesized in ARC (synthesized in white adipocytes)
What receptor does alpha-MSH bind to to inhibit the Agrp/Npy neuron?
MC3R
What receptor does alpha-MSH bind to to activate a secondary catabolic neuron in the PVN?
MC4R
What receptor does NPY bind to on a PMC/CAR neuron to inhibit it?
Y1R
What receptor does NPY bind to on a catabolic second order neuron in the PVN?
Y1R
What receptor does NPY bind to on an anabolic neuron in the LHA?
Y1R
What receptor does alpha-MSH bind to on an anabolic neuron in the LHA to inhibit?
MC4R
In what way(s) does AgRP stimulate feeding?
It inhibits alpha-MSH from inhibiting LHA (i.e. blocks inhibitory effect of alpha-MSH on the LHA) by acting as an inverse agonist and binding teh MC4R (thus, inhibiting PVN)
What receptors does alpha-MSH signal through?
MC3R and MC4R (melanocortin receptors)
How does AGRP anatognize alpha-MSH?
Acts as an inverse agonist (decreases PVN activation to the extent that alpha-MSH would increase it) and competes for the MC4R in the presence of alpha-MSH
What receptor does NPY signal through?
Y1R
What is the name of the ghrelin receptor?
Ghsr
What is GABA?
WHen Npy/Agrp neurons are activated by ghrelin, they release GABA. GABA binds to GABAnergic receptors on POMC/CART neurons, which inhibits the neuron, leading decreased PVN activation
What neuropeptides do secondary catabolic neurons in the PVN release?
Corticotropin releasing hormone and cocaine-amphetamine regulated transcipt
What neuropeptides do secondary anabolic neurons in the LHA release?
Orexin and melanin concentrating hormone
What is CB1R?
g-protein coupled cannabinoid-1 receptor
Is the CB1R anabolic or catabolic?
Anabolic…the munchies
In what ways does activation of NPY/AGRP neuron in the ARC by ghrelin increase feeding behavior?
1) Release of NPY, acting on Y1 receptors on the POMC/CART neurons and the Y1R in the PVN to inhibit the both of them 2) Release of AGRP antagonizes the MC4R in the PVN, inhibiting it. 3) NPY activating MC4R on LHA second order neurons, releasing ORX and MCH, which work on higher cortical areas and reward centers to increase appetite 4) Release of GABA, which inhibits the POMC/CART neuron by binding to a GABAnergic receptor
In what ways does activation of a POMC/CART neuron in the ARC by various factors decrease feeding behavior?
1) Activation of the POMC/CART neuron leads to release of alpha-MSH, which binds to MC3R on NPY/AGRP neurons, inhibiting it, and thus relieving its inhibition on catabolic neurons 2)Release of alpha-MSH binds to MC4R on second order neurons in the PVN, leading to release of CRH and CART, which suppress appetite and increase energy expenditure 3) Alpha-MSH binds to MC4R on second order neurons in the LHA, inhibiting them
Is serotonin anabolic or catabolic?
Catabolic
What is the serotonin receptor?
5-HT receptor
What is CRH?
corticotropin releasing hormone
What is ORX?
Orexin/hypocretin
What is MCH?
melanin concentrating hotmone
What neuropeptides do PVN secondary neuron release?
CRH and CART
What neuropepetides do LHA secondary neurons release?
ORX and MCH
What would a CB1 receptor antagonist do?
An endocannibinoid receptor antagonist. Has an anorexigenic effect on the hypothalamus
What genes in the lepton-melanocortin pathways when mutated cause monogenic obesity in humans?
Leptin, Leptin Receptor, POMC, PC1, MC4R or MC3R, SIM1
Satiation?
processes that promote meal termination, thereby limiting meal size (rapid and acute)
Satiety?
postprandial events that affect the interval to the next meal, thereby limiting meal frequency (also influenced by learned habits)…how long you feel full
Satiation factor criteria?
1) Factors should be released during food ingestion 2) Exogenous administration should decrease meal size in a dose-dependent manner – rapidly, transiently and at physiological concentrations without causing illness
Adiposity (negative-feedback) signal criteria?
1) Circulates at levels proportionate to body fat content and enters the brain 2) Promotes weight loss by acting on neuronal systems implicated in energy homeostasis 3) Blockade of the neuronal actions increases food intake and body weight
Only adiposity singals?
Leptin and insulin
Intestinal peptides that decrease food intake?
CCK, GLP1, oxyntomodulin, PYY
Pancreatic peptides that decrease food intake?
Pancreatic peptide and insulin and amylin
What cells in the small intestine sense nutritive and non-nutritive properties of luminal food and release satiation peptides from their basolateral aspect in response?
Enteroendocrine cells
All of the following are true regarding AgRP except: a) synthesized in the ARC b) stimulates appetite c) inhibits anorexigenic/catabolic neurons in the hpothalamus d) secreted in response to ghrelin e) increases energy expenditure
e) increases energy expenditure
Which of the following is false? a) mutation of leptin gene causes monogenic obesity b) mutation of leptin gene would increase feeding c) mutation of leptin gene would increase alpha-MSH d) mutation of leptin gene would increase fasting insulin levels e) mutation of leptin gene would decrease activity of PVN neurons
c) mutation of leptin gene would increase alpha-MSH
What receptor do GLP-1 and OXM work on?
GLP1R
What receptor does PYY work on?
Y2R
What is the site of action for PYY?
Vagus nerve to the NTS and the bloodstream to work on the hypothalamus
What is the site of action for oxyntomodulin?
Vagus nerve to the NTS and the bloodstream to work on the hypothalamus
What is the site of action for GLP-1?
Vagus nerve to NTS and bloodstream to work on the hypothalamus
What is the site of action of CCK?
Vagus nerve to the NTS only
Where do cell bodies of afferent fibers of the abdominal vagus nerve project onto?
The NTS of the brainstem
What does gastric load in the stomach stimulate?
Stimulates mechanosensitive fibers confined to the stomach dose-dependently which suppresses meal size. Mela suppression by gastric load occurs independently of the nutrient content of the load.
What does CCK do?
Directly activates vagal afferent fibers sensitizing them to subsequent distension and results in pyloric contraction and slowing of the gastric emptying
What gut satiation hormones are cleaved from proglucagon?
GLP-1 and Oxyntomodulin
What are GLP-1 and ocyntomodulin co-secreted with from the intestine?
PYY
What do GLP-1 and OXM bind to in the brainstem and hypothalamus?
Bind to GLP-1 receptor
What is the PP-fold family, and what are some examples of proteins in this family?
36 aa in length and share a common structural motif known as the PP-fold…NPY, PYY, PP
What receptor does PYY bind to, and what does it do?
Binds to Y2 receptor isoform and decreases food intake
What does PP do, and how does it differ from other satiation factors?
Acutely reduces food intake but the effect remains for up to 24 h in contrast to other satiation signals (i.e. CCK). Chronic exposure to PP does not diminish the anorectic effects (i.e. no development of PP resistance)
What receptor does PP act through?
A Y receptor isoform…Y4
Mice with mutation of leptin?
ob/ob mice
Mice with mutation in leptin receptor?
db/db mice
ob/ob and db/db mice have what characteristics?
Obesity and diabetes. Weigh 3X more than normal mice and have 5X higher body fat content (even when fed the same diet). Display hypothyroidism, decreased growth, infertility and decreased immune function (i.e. neuroendocrine starvation response)
When injected centrally, leptin causes weight loss…what does this show?
Shows that leptin isn’t crossing the blood brain barrier in obesity
Why is leptin efficacious during fasting induced weight loss?
Body still thinks it is fat, so it still suppress feedings (i.e. ghrelin)
What is a possible strategy to cirumvent leptin resistance?
Ciliary Neurotrophic Factor
What is STAT 3, and what does it do in leptin signaling?
Signal Transducer and Activator of Transcription…decreases transcription of AgRP and increases transcription of POMC
What is SOCS3, what does it do, and what activates it?
Suppressor of Cytokine Signaling, negative feedback to turn off the leptin receptor by inhibiting JAK and SHP-2, and it is activated by phosphorylation of Tyr1138 (which activates STAT 3, thus increasing transciption of SOCS3)
What is JAK, and what does it do in the leptin signal pathway?
Janus Kinase…physically binds to ObR –? autophosphorylates its own tyrosine residues which activate the enzyme, this activating numerous cascades
What is SHP-2, and what does it do in the leptin signaling pathway?
Src homology-containing typrosine phosphatase 2…activated by phosphorylation of Tyr985 and it activates the ERK 1/2 pathways, leading to a decrease in NPY/AgRP neuron firing and an increase in POMC neuron firing
What activates the IRS-PI3K pathway in leptin signaling and what does it do?
Activated by phosphorylation of the proximal tyrosine on the leptin domain. Leads to a decreaes in AgRP protein and increased POMC protein and may also increase POMC neuron firing
How does leptin regulate POMC and AgRP gene transcription?
They activate STAT3, which decreases AGRP protein expression and increased POMC protein expression
How does insulin regulate POMC and AgRP regulate gene transcription?
Activates the IRS/PI3K pathway, leading to activation of PKB. PKB inhibits FOXO1. Because FOXO1 usually increases expression of AgRP and decreases expression of POMC, inhibiting it relieves this inhibition leading to an increase in POMC and a decrease in STAT3
In s/s mice (LRb S1138), what are the effects?
Increased feeding and decreased energy expendiure, profound obesity like db/db, decrease in POMC but normal NPY, leptin still decreases AgRP/NPY activity, retain fertility/growth/immune functions
What are the effects of a LRb L985 mutation (l/l mice)?
Decreased feeding and adiposity and decreased NPY and AgRP levels
Why are l/l mice (LRb L985) resistant to diet induced boesity?
It reduces the activation of SOCS3, and therefore there is less leptin inhibition from JAK = less leptin resistance
What is AMPK?
AMP Activated Protein Kinase…important downstream target of leptin signaling that mediates the anorexigenic effects of leptin
What receptor family does Lrb?
Belongs to the IL-6 Receptor Family of Class 1 Cytokine Receptors
What does AMPK activation do?
Catabolism/energy production to restore energy balance
What stimulates AMPK?
Metabolic stress such as hypoxia, glucose deprivation and metformin
What does AMPK inhibit?
Increased ATP consumption such as cell growth and division, activation of motor proteins.
What is the structure of AMPK?
Hetertrimetric cimplex (alpha, beta and gamma subunits)
How is AMPK activated?
Activated by upstream kinases such as LKB1 and CaMKK via phosphorylation of Threonine 172
What can acitvate CaMKK?
Anything that causes an increase in intracellular calcium levels
What are some things that can increase AMPK activity?
ghrelin, fasting and AICAR…increases AMPK, increases NPY, leading to an increase in food intake and decreased energy expenditure
What are some things that can decrease AMPK?
Leptin, fed state, insulin…decreased NPY, leading to a decrease in food intake and increased energy expendiure
How does AMPK reduce food intake?
Leptin/insulin/glucose/alpha-linolenic acid bind to their receptors and decrease AMPK activity –> decreased ACC phosphorlyation, which increases its activity –> increased production of malonyl-CoA –> inhibits CPT-1 –> less mitochondrial fatty acid –> less beta-oxidation and accumulation of long chain fatty acid CoA in the cell –> decreased food intake
How does ghrelin activate AMPK in the hypothalamus?
Ghrelin binds to its receptor –> phosphorlyates and thereby activates AMPK –> phosphrylation of ACC, which decreases its activity/inhibition of ACC –> decrease in malonyl-CoA –> increased CPT-1 –? increased fatty acid oxidation –> decrased long chain fatty acid CoA in the cell –> increased food intake
What is the pulsatile pattern of ghrelin?
Levels rise sharply just before meals or wiht food restriction or starvation and they call rapidly after meals. Circulating ghrelin also plays a role in long term energy balance and body weight regulation because it increases with weight loss and decreases with increased adiposity
Hoe does initiate cell depolarization in AgRP/NPY neurons?
It binds to its receptor, which initiates a G-Protein coupled signaling cascade that results in cell depolarization…increases intracellular calcium which also stimulates AMPK and that whole cascade of increases food intake
