Mammalian Endo Exam 2

• T4 or thyroxine is most abundant.
• T3 or triiodothyrone most biologically active.

T4 has 4 iodine molecules whereas T3 only has 3.

During the peri-natal life along with the early neonatal period.

Everywhere! Probably in all tissues in body at some time or another

• skeletal muscle
• cardiac muscle
• liver
• gastrointestinal tissue
• kidney

Iodine

Iodine is a rare element, present in ocean water but unevenly distributed in soils of world land masses

• increased BMR
• elevated cardiac output
• elevated body temperature
• inappropriate sweating
• weight loss associated with muscle catabolism

• reduced BMR
• enlarged heart with reduced cardiac output
• decreased body temperature (reduced sweating)
• myexdemia (accumulation of fluids  protein under the skin)

Very large protein in follicular cells that has tyrosine residues & can be ionated

inside of colloids (inside of cell)

homogenous granules that contain secretory products, primarily thyroglobulin

• dietary absorbed by GIT (converted to inorganic iodide)
• -transported by plasma proteins
• -upake by thyroid via active transport
• -TSH importan for iodide uptake

causes uptake of I to be temporarily blocked

• TSH binding causes pinocytosis of Tg
• -releases T3 & T4
• binds to receptor on thyroid gland & increases synthesis via several different mechanisms
• tyrosine molecules get pinocytosed & released to peripheral tissue

• increased blood flow (angiogenesis)
• increased thyroglobulin synthesis
• increased trapping mechanism for iodine

• increased T3/T4 levels shut down thyrotroph cells of pituitary
• T3/T4 concentrations sensed by pituitary & regulates presence of TRH receptor
• most direct feedback is to thyrotrophs of pituitary

• TSH antibodies can interact with TSH receptors, increasing T3/T4 synthesis = hyperthyroidism
• TSH is bound by antibody, no interaction with receptor, lots of TSH being released but not used = hypothyroidism

• Hyper = downregulates TRH receptor & decreases sensitivity of gland
• Hypo = upregulates TRH receptor & increases sensitivity of pituitary to increase release of TSH

• sensitivity of TSH dependent on feedback mechanism at pituitary level
• TRH receptors regulate
• T3/T4 feedback & change TRH released from hypothalamus
• feedback at pituitary level, sensitivity of pituitary glands to TRH is what changes

Bound to proteins

0.4%

Free form is required for biological response

• thyroxine binding globulin (TBG) - 75%
• throxine-binding prealbumin - 20%
• albumin -5 - 10%

• T3 is 3 - 5X more biologically active
• T3 has a small vascular pool with a high turnover & is found in higher concentrations in target tissues
• T4 has a large vascular pool with a slow turnover

• cellular differentiation & development
• mammary development
• metabolic actions

• TSH can be regulator of GH
• GH secretion diminished in absence of thyroid hormones
• thyroid hormones induce GH & IGF production (especially in cases of disease)

• neuronal proliferation & differentiation
• myelinogenesis
• neuronal outgrowh
• synapse formation

• is low, supplementation is required
• fetal thyroid functional at ~11 weeks
• fetus does not receive much T3 or T4 from mother

• protein synthesis & degradation
• fat synthesis & degradation (cholesterol synthesis & LDL receptors)
• carbohydate metabolism (increases rate of absorption of glucose from GI, glycogen synthesis & degradation)

• increased HR, myocardial contractility & cardiac output (increased stroke volume)
• hyperthyroidism increases HR & stroke volume
• hypothyroidism decreases HR & stroke volume

• T3 is increased during short-term overfeeding
• plasma T3 decreased during prolonged fasting
• starvation diet = reduced calorie intake = decreased amount of thyroid hormone due to reducing amount of heat produced

increased beta-adreneric receptorsin heart muscle, skeletal muscle, adipose tissue & lymphocyte

increased bone turnover

stimulates gut motility

increases tissues ability to interact with those hormones

there are 5 isoforms

nuclear receptor that interacts with transcription factors

• rat GH
• oxytocin
• nerve growth factor (NGF)
• myosin heavy chain (alpha)
• myelin basic protein
• PEP carboxy kinase
• Ca ATPase
• Na/K ATPase
• cytochrome oxidase
• HMG-CoA reductase

• human GH
• TSH
• EGF receptor
• myosin heavy chain (beta)

both

increased TSH secretion - attempt to stimulate iodide-trapping mechanisms & intrathyroidal metabolism of iodine

excess thyroid hormones that cause autoimmune disorder

• eyeball bulging due to accumulation of fluid & connective tissue substance
• goiter & skin thickening

development of TSH-antibodies that mimic action of TSH production; long acting thyroid stimulator

hypothyroidism

• accumulation of fluids in face & periphery
• mental deficiency occurs often

• loss of functional thyroid tissue (Hshimoto's disease)
• biosynthetic defects in hormonogenesis (inherited, iodine deficiency, anti-thyroid agents)
• TSH or TRH deficiency
• peripheral resistance to thyroid hormones

Autoimmune thyroiditis with early onset

the gut

digestion & moving food along tract

• cause release of enzymes which are necessary to breakdown food substances
• stimulate secretion of acids and/or bicarbonate (ensure pH optimum for enzyme activity)

traditional hormone messengers & neurotransmitters

• release of ions, water & bicarbonate to optimize gut pH
• release of enzymes for splitting food molecules

secretin

immunochemical techniques

• CCK
• gastrin
• secretin

• polypeptide
• somatostatin

• CCK
• polypeptide
• GLP-1
• polypeptide Y (PPY)
• ghrelin

• cholecystokinin
• duodenum & jejunum
• presence of peptides & FA causes gall bladder to release
• stimulates GI motility
• increases GI blood flow

induction of satiety

• gallbladder contraction
• pancreatic enzyme secretion (pancreatic exocrine secretion)
• gastrointestinal motility

produced by endocrine cells in proximal intestine & by neurons in central & peripheral nervous system

• stomach hormone
• food in the gut is primary stimulus of gastrin release
• stimulates HCl & pepsinogen release
• stimulates GI motility
• increases GI blood flow

acid secretion

stimulate acid secretion by gastric parietal cells

• acidification of gastric contents
• somatostatin

growth of gastric mucosa

• release of HCl in response to distension of stomach & presence of nutrients causes gastrin to be released from histamine
• produced by endocrine cells in gastric antrum

• partially digested peptides & AAs
• vagus nerve stimulation
• bombesin/GRP

• duodenum & jejunum
• 1st released from acid-chyme
• exocrine causes pancreas to release bicarbonate & pH increases
• inhibits GI motility
• increases GI blood flow

Pancreatic exocrine secretion

• stimulates pepsin secretion for the breakdown of peptides
• inhibits secretion of gastric acid
• inhibits GI motiltiy

stimualates secretion of water & bicarbonate ions by exocrine pancreas

endocrine S cells in proximal intestine

• inhibits GI endocrine secretion
• inhibits GI motility
• endocrin from pancreas
• GHIH inhibits gastrin in stomachinhibits GI motility

• affects all major functions including endocrine secretion & gut motility
• inhibits insulin &/or glucagon secretion
• inhibits gastrin secretion (& HCl)

exclusively inhibitory effects

hypothalamus, GI tract, pancreas

• enteroglucagons
• role in insulin regulation
• ileum

• induces differentiation of beta cells in vitro from stem cells
• agonist (exenatide) used to treat type II diabetes

response to carbohydrates, fat in GI tract

• inhibits gastrin
• stimulates liver glycogenolysis
• stimualates pancreatic release/synthesis of insulin
• incretin activity
• satiation

• enteroglucagonsrole in insulin regulation
• ileum

co-secreted with GLP-1

satiation

• trophic effects on intestines
• gastrointestinl motility & growth

• Gastrin-inhibiting peptide, aka glucose dependent insulintropic peptide
• duodenum & jejunum
• inhibits GI motility

oral glucose & AAs

in proximal intestine

• inhibits gastric acid secretion
• stimulates insulin secretion/synthesis

• duodenum & jejunum
• keeps gut moving when fasting
• stimulates GI motility

presence of nutrients in SI

fasting

• stimulates GI motility
• increased GI blood flow

• role in appetite regulation
• enteroglucagon in ileum
• endocrine from pancreas

• inhibits pancreatic exocrine secretion & bile secretion
• inhibits gastric emptying; reduces food intake
• gastric motility
• satiation

• hunger
• growth hormone relese

endocrine from pancreas

• endocrine from pancreas
• inhibits GI motiltiy
• increases GI blood flow

Acinar cells are source of digestive enzymes; digestive enzymes reach small intestine through ducts

• reservoir for bile salts excreted from the liver
• bile salts allow for emulsification of fats in the SI

gastrin

• CCK
• secretin
• GIP
• motilin

• GLP (1&2)
• PPY

• insulin
• glucagon
• pancreatic polypeptide
• somatostain

• exocrine secretions
• motility
• endocrine secretion
• blood flow

regulate secretion & absorption of water, electrolytes, enzymes & mucus

• bombesin (GRP, stimulator) & somatostain (inhibitor)
• inhibitory effects on gastrin release are mediated by an increase in somatostatin

• stimulate (gastrin, CCK, motilin, bombesin (GRP), neurotensin)
• inhibit (glucagon, VIP, GIP, secretin, somatostatin)

Gastrin, CCK, secretin, glucagon, VIP, substance P, neurotensin

• US - 97 million obese
• 2 of 3 overweight
• 1 of 3 obese
• ~5% of US population is extremely obese
• obesity has increased 3X in last 30 years
• WHO classifies it as an epidemic

• Obesity: high energy in, low energy out
• Anorexia: low energy in, high energy out

• Arcuate nucleus
• paraventricular & ventromedial
• lateral hypothalamic area
• brainstem

• it is the feeding control center
• integrates hormonal signals for energy homeostasis
• circumventricular organ

satiety centers

• glucose sensitive neurons
• stimulate feeding in response to hypoglycemia

vagus nerve

important connections with taste centers & hypothalmus

reciprocal connection

• nucleus of tractus salitarius
• high density of NPY (neuro-peptide Y) binding sites
• NPY content in NTS varies with feeding
• connects with PVN

• satiety signals
• role in individual meal size

limbic structures that have reciprocal connections to hypothalamus

• energy intake varies & body weight conserved
• food intake (meal size & frequency) must be conserved

• leptin
• insulin

• ghrelin
• PYY (peptide YY)
• PP (pancreatic polypeptide)
• CCK (cholecystokinin)
• Oxm (Oxyntomodulin)
• GLP-1 (Glucagon-like peptide 1)

ghrelin

• PYY
• PP
• CCK
• Oxm
• GLP-1

• Orexigenic tells you to eat (hunger signal)
• Anorexigenic tells you to stop (satiety signals)

• Anorexia is lack of appetite
• Anorexia nervosa is a disease condition

integrates signals from peripherystimulates (NPY & AgRP) or inhibits (CART & POMC)

Summary of central pathways involved in appetite regulation

orexigenic

stomach

circulating levels upregulated by fasting

• gut nutrients (not just amount)
• glucose load but not volume suppresses ghrelin

No, ghrelin is affected by gut nutrients, not just amount in stomach

Plasma levels are high in fasting & drop after eating

NPY neuron

Yes, can increase feed intake by 28% but there is no difference in satiety

• inverse relationship
• lower ghrelin levels in obese subjects

• when food intake does not suppress ghrelin
• hyperphagia
• extreme obesity
• hypogonadism
• short stature
• mental retardation

peptide in NPY family

distal gut (L cells in crypt)

causes marked inhibition of food intake

secretin

decreases both

inhibits release of NPY & stimulates release of alpha-MSH

binds to Y2R receptor on NPY neurons

• shortly after food intake as a neural response to gut fill
• released again when food reaches distal SI

carbohydrates & fats

GLP-1

• decreases gut motility
• leads to sensation of fullness & satiety

obese people have lower basal fasting PYY & have smaller rise after eating

pancreatic cells

low levels during fasting

increase through all phases of digestion

decreases food intake by 22%

• decreases gastric emptying & appetite
• increasing energy expenditure

produced from cleavage of preproglucagon in gut & brain

acts on GLP-1 receptor

decreases food intake by 20%

• is a GLP-1 receptor antagonist that blocks oxm actions
• binds with very weak affinity

produced from preproglucagon in gut & brain

acts at pancreas to release insulin

inhibits

• inhibits food intake
• increases energy expenditure

increases food intake

levels achieved post-meal have a small affect on appetite

• improve glycemic control
• decrease body weight

duodenal cells in response to chyme

CCK

fat & protein

reduces meal size & postprandial hunger

• NPY stimulates
• POMC inhibits

adipocyte hormone

levels are proportional

inhibits

binds to receptor in hypothalamus

• inhibits NPY/AgRP
• stimulates POMC

weight loss starvation associated with low energy expenditure, hyperphagia, & low leptin levels

no, it is relatively insenstive

leptin has role in regulation of GnRH

• starvation reduces transport
• refeeding increases transport

• ob = mutation in gene for leptin
• db = mutation in gene for leptin receptor

• leptin resistance & obesity may occur at level of BBB
• obese individuals have much lower level of leptin in CSF than in serum
• possible that triglycerides block transport

pancreatic beta cells

• regulates energy balance
• essential for adipose tissue formation

levels are proportional to body mass

• obesity associated with insulin resistance
• precedes development of diabetes

decreases

receptor-mediated process

anorexigenic

NPY & POMC neurons

orexigenic

• low leptin
• hypoglycemia
• hypoinsulinemia
• negative energy balance

• inhibits thermogenesis
• increases food intake
• promotes adipogenesis

5 (Y1, Y2, Y3, Y4, Y5)

Y1, Y2 & Y5

• NPY was necessary to stimulate foraging behavior
• anorexics have increased movement pathology & high NPY

• Agouti Related Peptide
• agouti is a protein associated with hair follicles

in the arcuate nucleus

• antagonizes MC-3 & MC-4 receptors (MSH receptors)
• stimulates appetite

orexigenic

cocain & ampethamine regulated transcript

Pre-opiod melanin

anorexigenic

anorexigenic

alpha-MSH (also ACTH)

red hair, adrenal insufficiency, early onset obesity

MC3R & MC4R receptors

severe obesity, hyperphagia, hyperinsulinemia, increased fat-free & linear growth

• agonist inhibits feeding
• antagonist causes hyperphagia

co-localized with POMC neurons in the arcuate nucleus

anorexigenic effects of leptin

GLP-1

blockage of GLP-1 receptors inhibits CART-induced hypophagia

increases CART in ob/ob mice

orexigenic

• provide palatability & rewarding aspects of feeding
• not necessary for energy need

localized in brain (pleasure centers; limbic system) as well as hypothalamus, GIT & adipose tissue

increases both with repeated administration

• converts POMC to ACTH
• affects synthesis of alpha-MSH, leading to hyperphagia

melanocortin 4 receptor

• increased PYY & GLP-1
• improved satiety & improved insulin sensitivity
• hormonal changes noted before weight loss

adipose tissue

adipose tissue

• leptin
• adiponectin
• steroid hormones
• retinol binding protein
• visfatin
• resistin
• pro-inflammatory cytokines

passive organ that plays metabolic role in energy homeostasis

• stores energy as triglycerides
• releases energy as fatty acids

synthesizes & secretes hormones & adipokines

type-2 diabetes & cardiovascular disease

endothelium, muscle, liver, pancreas, adrenal glands, central nervous system

fatty acids, prostaglandins, steroids, proteins

by adipocyte number & size

hypertrophy

triggers differentiation of precursor cells into mature adipocytes (triggers stem cells)

• large cells are less sensitive to insulin & have a higher rate of lipolysis
• large cells have increased leptin production
• cell size gives difference in gene expression

positively correlated with increased BMI

increase secretion of pro-inflammatory cytokines from adipose tissue

multipotent mesenchymal stem cells & preadipocytes

severe obesity, insulin resistance, impaired thermogenesis

yes with leptin treatment

• defective transport (crossing BBB)
• defects in leptin signalling (leptin resistance)
• antibody to leptin

a very large protein

• mature adipocytes
• higher levels in subcutaneous fat

resistance is at the receptor & transport so you can't supplement & correct problem

collagen superfamily

lower

• AdipoR1
• expressed in muscle, hypothalamus co-localized with leptin receptor
• AdipoR2
• expressed in liver, hypothalamus co-localized with leptin receptor

7-transmembrane domains

reduced serum levels

• adiponectin binding to its receptor activates specific intracellular pathways
• increased glucose uptake & fatty acid oxidation in muscle
• increased fatty acid oxidation & decreased gluconeogenesis in liver

• downregulates expression of vascular adhesion molecules
• inhibits endothelial NFkB
• inhibits monocyte adhesion to vascular wall

adiponectin

• Retinol binding protein 4
• a specific circulating transport protein for retinol

impairs signaling at the muscle

increased

• inflammation
• fatty liver disease
• insulin resistance

• detects absence of glucose by GLUT4 & responds by secreting RBP4
• RBP4 inhibits insulin signaling

• decreases PI3 kinase in muscle
• inhibits phosphorylation of insulin receptor substrate-1 in muscle
• gluconeogenic enzymes are upregulated in liver

peptide hormone

adipocytes in rodents & macrophages in humans

increase with both

adiponectin

increased

increased hepatic glucose production in response to infusion or over-expression of resistin

obesity-induced hyperglycemia

produced by macrophages in adipose

upregulated

increase

• insulin-mimetic effects
• stimulates glucose uptake & triglyceride incorporation
• rbVisfatin lowered plasma glucose in mice
• binds to & activates insulin receptor

• tumor necrosis factor alpha (TNFalpha)
• transforming growth factor beta (TGFbeta)
• interferon-y
• interleukins - IL6
• monocyte chemotactic protein
• factors of the complement cascade

increase with increased obesity

• P450 aromatase
• 11beta-HSD1

• converts androstenedione to estrone
• converts testosterone to estradiol

converts cortisone to cortisol

Celsus, 10AD

Aretaeus, 20AD

Cawley, 1788

Langerhans, 1869

Von Mering & Minkowskie, 1889

Banding & Best, 1921

• disorder characterized by polyuria
• sweet

abnormally high

• type I is insulin-dependent
• type II is non-insulin dependent

• leading cause of kidney failure, lower-limb amputation, & blindness among adults
• major cause of heart disease & stroke
• 7th leading cause of death

endocrine function in nests of pancreatic cells called islets of Langerhans, composed of several different cell types each secreting a separate hormone

• Alpha cells - glucagon
• beta cells - insulin
• delta cells - somatostain
• f cells - pancreatic polypeptide

pancreatic juice contains digestive enzymes

• controlled by reflex mechanisms after a meal
• controlled by gastrointestinal hormones secretin & CCK

• muscle
• liver
• fat
• hypothalamus

liver

pancreatic beta cell

pancreatic alpha & beta cells

inside of liver cell

• feeding potent stimulus for insulin release
• exercise & fasting potent stimulants for glucagon secretion

anabolic - energy storage

transport of glucose & amino acids into cells

precursor forms into storage forms

glycogen, protein, triglycerides

elevated blood levels of glucose (mainly) but also fatty acids or amino acids

• GI tract motility & stimulation by the parasympathetic nerves
• activation of insulin secretion by acetyl choline
• presence of CHOs in intestine causes release of GIP, insulin secretagogue & GLP-1

• promotes storage of glucose, fatty acids, & inhibits breakdown of glycogen & triglycerides
• blocks or reverses effects of other hormones
• activates phosphatases that remove phosphate from enzymes resulting in deactivation of that enzyme
• reverses phosphorylation induced by cAMP-dependent protein kinases

recruits glucose transport protein of GLUT4 in liver & muscle

• insulin internalized & degraded
• receptors are not degraded but are recycled back to membrane
• action on cell to increase rate of glucose uptake

• seconds - binds receptor, Tyr-Kinase activity
• minutes - hexose transport, altered enzyme activity, gene regulation, receptor internalization & down regulation
• hours - induction of DNA, RNA, protein & lipid synthesis, cell growth, down regulation of insulin receptor

alpha cells of pancreas

elevate blood glucose levels

catabolic - stimulates liver glycogenolysis & inhibits glycolysis

epinephrine

enzymes become phosphorylated & active in pathways

stimulates gluconeogenesis in liver

• increased glucose in blood
• loss of glucose through the kidney
• increased loss of water
• increased thirst

• retinopathy
• neuropathy
• nephropathy
• fatty liver

• Insulin - type I has lack of insulin, type II beta cells do not produce sufficient insulin
• Cause - type I caused by destruction of beta cells, type II caused by resistance of insulin receptor
• Development - type I rapid onset, type II gradual development
• Age - type I usually before 35 years & most often between 10 - 16 years, type II usually over 40 years
• Statistics - type I 10% of all diabetics, type II 90% of all diabetics

• 50% of adults >65 have pre-diabetes
• increased incidence of central obesity
• oxidative stress & mitochondrial dysfunction

black americans & pima indians have increased risk over caucasians

• persistently elevated FFA levels leads to systemic insulin resistance
• adipose tissue dysfunctions contribute to elevated FFA
• may contribute to inflammation

• controlled by insulin
• increased FFA with fasting, decreased after meal

• age
• genetic backgroun
• lipotoxicity
• endoplasmic reticulum stress
• hypoxia
• oxidative stress
• inflammation
• adipokines
• hyperinsulinemia
• hyperglycemia
• resistin

• accumulation of unfolded proteins causes ER stress
• glucose, viral infections, hypoxia & lipids inhibit protein folding
• drugs which relieve ER stress improve insulin sensitivity in liver

• obstructive sleep apnea associated with insulin resistance in obese
• may contribute to inflammatory response

• reactive oxygen species (ROS) generated by mitochondria during oxidation of FA & glucose for ATP
• oversupply of FA & glucose in obesity causes oxidative stress
• exercise may increase ROS but improved insulin sensitivity

• chronic, low-grade inflammation associated with obesity
• inflammation inhibits insulin signalling
• reduction of lipid synthesis by decreased PPARy & increased FFA
• muscle insulin sensitivity is not sensitive to inflammation

• leptin inhibitory for insulin synthesis & secretion but at high levels, leptin appears to be stimulatory
• adiponectin decreases with increased obesity; adiponectin protected beta cells from apoptosis in face of elevated glucose

• over production & decreased clearance
• role of leptin

• increased glucagon synthesis & release
• proliferation of alpha cells
• increased production of liver glucose

• decreased insulin receptors in beta cells
• cause insulin resistance in pancreatic islets

increases the likelihood of obesity

• 43% are obese as adults
• 29% are overweight
• 28% become normal weight