Introduction 1. 2. A. B. C. 3. BMI 1. 2. 3. 24 27 4. 30
Slide 3
Introduction Control mechanisms of food intake
Slide 4
Introduction 1. A. Lateral hypothalamus B. Medial hypothalamus
2. Arcuate nucleus -MSH -MSH AgRP 3. Neuropeptide Y NPY
Slide 5
Body weight regulation Mechanism (Peripheral) Ghrelin
(Stimulates food intake) The only orexigenic GI peptide Act on GH
secretagogue receptor Secreted by oxyntic glands in stomach The
major endogenous ligand for GH secretagogue receptor CCK GLP-1 PYY
3-36 (Suppresses food intake) Enhances satiety GLP-1 (Lowers blood
sugar) Insulin release Glucagon release Inactivated by DPP IV
Slide 6
Body weight regulation Mechanism (Peripheral) Strategy for
anti-obesity by modulating peripheral mechanism PYY 3-36 receptor
agonist GLP-1 agonist (Exenatide) DPP IV inhibitor CCK-A agonist
Ghrelin antagonist
Slide 7
Body weight regulation Mechanism (Central) Neuropeptide Y (NPY)
1.Most powerful central enhancer of appetite A.Predominantly
expressed in arcuate nucleus B.90% of NPY neurons co-express AgRP
2.NPY1R & NPY5R mediate NPY anabolic effect A.NPY1R & NPY5R
antagonist could suppress orexis 3.Side effects A.Hypertension
Analgesia Hypoglycemia B.Impairment of pituitary hormone secretion
4.Expression of NPY in arcuate nucleus A.Leptin level
B.Hypoglycemia C.Hyperinsulinemia 5.Major function A.Thermogenesis
B.Food intake C.Adipogenesis
Slide 8
Body weight regulation Mechanism (Central) Agouti-related
protein (AgRP) 1.A potent orexigenic peptide 2.Its release by
arcuate nucleus is inhibited by leptin 3.Upregulated expression in
ob/ob mice (Leptin knockout mice) 4.Obesity A.High level of AgRP
B.Related to polymorphism of AgRP gene (G199A)
Slide 9
Body weight regulation Mechanism (Central) Proopiomelanocortin
(POMC) Precursor of MSH (Melanocyte stimulating hormone) The major
regulator of energy balance Anorexigenic effect of MSH is mediated
by MC3R (Melanocortin 3 receptor) & MC4R which are expressed in
arcuate nucleus The effect of POMC could be blocked by MCR
antagonist 5% obesity MC4R gene mutation
Slide 10
Body weight regulation Mechanism (Central) Cocaine- &
Amphetamine-related transcript (CART) 90% of CART & POMC are
both expressed in the same neuron of arcuate nucleus Related to
anorexigenic effect of leptin CART null mice develop increased food
intake & obesity
Slide 11
Body weight regulation Mechanism (Central) Leptin An
adipocyte-derived satiety factor A cytokine that acts on gp130
family of cytokine receptors in the hypothalamus to activate
Jak/Stat In the hypothalamus Leptin binds to long form of leptin
receptor (ObRb) Jak2 Stat3 Control expression of anorexic &
orexic peptides
Slide 12
Body weight regulation Mechanism (Central) Leptin Anti-obesity
Energy expenditure Food intake Leptin resistance Attenuation of
leptin action in obese rodent & human Appetite Energy
expenditure Plasma leptin Leptin is also important in regulating
the onset of puberty Leptin deficiency is associated with
hypogonadism
Body weight regulation Mechanism (Central) Long-term mechanisms
Neural & Humoral signals derived from periphery are integrated
in specific regions of hypothalamus & brain stem Energy
homeostasis is maintained by balance between Stimulate food intake
& Promote weight gain (Anabolic or Orexigenic) Promote reduced
food intake & Depletion of body fat (Catabolic or Anorexigenic)
Strategy for anti-obesity by modulating central mechanism Block
orexigenic neuropeptides(NPY & AgRP) Enhance anorexigenic
hormones(-MSH & CART)
Slide 15
Body weight regulation Macrophage participation in obesity
inflammation
Slide 16
Body weight regulation Macrophage participation in obesity
inflammation 1. TNF- TNF- receptor 2. TNF- 3. TNF- Adiponectin 1.
sensitizer 2. 3. A. B. C. D. E.
Slide 17
Body weight regulation Centrally acting agents Anorexiants
Appetite-suppressing agents Targeting 3 monoamine receptor systems
in hypothalamus Noradrenergic receptor Dopaminergic receptor
Serotonergic receptor
Slide 18
Body weight regulation Centrally acting agents Anorexiants
Amphetamine Dual dopaminergic & noradrenergic re-uptake
inhibition Noradrenaline release & Its re-uptake Sibutramine
Dual serotonergic & noradrenergic re-uptake inhibition
Primarily affects satiation without addictive potential Elevation
of NPY & Decrease of POMC Lorcaserin 5-HT 2c agonist
(Restricted expression in CNS)
Slide 19
Body weight regulation Centrally acting agents The
endocannabinoid system Functions Feeding Pain Emotion Behavior
Peripheral lipid metabolism Endocannabinoids Anandamide
2-arachidonoylglycerol (2-AG) Increase food intake Cannabinoid
receptors CB1 (Abundant in brain) CB2 (Present in immune cell)
Slide 20
Body weight regulation Centrally acting agents The
endocannabinoid system Rimonabant Selective CB1 receptor antagonist
Adiponectin HDL Triglyceride LDL Fasting insulin Leptin Taranabant
Type 2 inverse agonist of CB1 receptor Also treat nicotine
dependence CB1 knockout are lean & resistant to diet-induced
weight gain
Slide 21
Body weight regulation Peripherally acting agents Lipase
inhibitors (Lipostatin) Produced by mold Streptomyces toxytricini
Reduce overall cholesterol Reduce LDL Raise HDL Lower triglyceride
Improve circulation
Slide 22
Body weight regulation Peripherally acting agents Lipase
inhibitors (Orlistat) A potent slowly reversible inhibitor of
pancreatic & gastric & carboxyl ester lipases &
phospholipase A 2 Reduce intestinal digestion of fat Minimally
absorbed from GI tract & primarily eliminated in feces No
systemic side effects Form covalent bonds with active serine
residues of lipase Rendering inactivated form unable to hydrolyze
dietary fat
Slide 23
Human skeleton Characteristics Cortical bone(80%) Dense &
Compact outer part The shafts of long bones Trabecular bone(20%)
Inner meshwork Vertebrae Epiphyses of long bones & iliac crest
More active & more susceptible to bone loss
Slide 24
Human skeleton Characteristics Bone minerals calcium salts
& phosphates > 99% of body Ca 2+ is in bone Mostly as
crystalline hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ) Osteoid
(Organic matrix of bone) Principal component Collagen Other
component Proteoglycans Osteocalcin Various phosphoproteins
Osteonectin Binds & Links Ca 2+ & collagen
Slide 25
Human skeleton Bone remodeling Osteoblast 1.The prime player in
forming the basic multi-cellular unit BMU in that it controls
osteoclast differentiation during cell-to-cell contact 2. OPGL RANK
A.OPG Osteoprotegerin B.RANK Receptor activator of NF-B 3.Bone
resorption by osteoclasts is regulated by osteoblasts via RANK/OPGL
signaling pathway A.OPG B.RANK C.OPG RANK OPGL Hormone regulation
1.The participation of cytokines IL-6 2.The turnover of bone
minerals Calcium & Phosphates 3.The actions of several hormones
A.Parathyroid hormone Calcitonin B.Growth hormone Vitamin D Steroid
4.Diet Drugs Physical factors Exercise Loading also affect bone
remodeling
Slide 26
Human skeleton
Slide 27
Bone remodeling FactorOPGRANKL TGF- PTH Glucocorticoid Vitamin
D 3 Estrogen 1.TGF NFB 2.PTH Glucocorticoid PTH Vitamin D 3
3.Glucocorticoid Estrogen
Slide 28
Human skeleton Bone remodeling
Slide 29
Human skeleton Osteoporosis Bone loss rate (0.5~1% per year)
Starts in 35~40 age group in both sexes Bone loss rate accelerates
10-fold during menopausal women (or men with castration) Then
gradually settles at 1~3% per year
Slide 30
Human skeleton Osteoporosis Bone loss during menopausal women
Osteoclast activity (Affects mainly trabecular bone) Later bone
loss in both sexes with increasing age Osteoblast numbers (Affects
mainly cortical bone) 3 osteoporosis-related indexes Excessive
glucocorticoid or thyroxine Postmenopausal deficiency of estrogen
Age-related deterioration in bone homeostasis
Slide 31
Human skeleton Mechanisms contributing to bone mineral
homeostasis
Slide 32
Slide 33
Human skeleton The turnover of bone minerals Calcium metabolism
1.[Ca 2+ ] A.Regulated by PTH Calcitonin B.Intracellular [Ca 2+ ]
(100 nM) Plasma [Ca 2+ ] (2.5 mM) C.Excretion through kidney
Absorption through small intestine 2.Ca 2+ absorption in intestine
involves A.Ca 2+ binding protein (The synthesis is regulated by
calcitriol) 3.High blood [Ca 2+ ] A.Urinary Ca 2+ excretion 4.Low
blood [Ca 2+ ] A.Urinary Ca 2+ excretion & Absorption of Ca 2+
from kidney by PTH & calcitriol B.Mechanism 1)Increases
secretion of PTH 2)PTH enhances synthesis of calcitriol 3)PTH &
Calcitriol enhances renal absorption of Ca 2+ 4)PTH &
Calcitriol enhances osteoclasts indirectly by acting on osteoblast
C.PTH enhances calcitriol while calcitriol suppresses PTH
Slide 34
Human skeleton The turnover of bone minerals Phosphate
metabolism 1.[P] absorption is an energy-requiring process
regulated by calcitriol 2.[P] A.Regulated by PTH Calcitriol FGF23
B.Excretion through kidney C.Skeleton is major storage pool for
phosphate & principal production site for FGF23 D.[PTH] &
[Calcitriol] determine whether phosphate deposit in bone or release
in blood
Slide 35
Human skeleton Hormones involved in bone metabolism &
remodeling Parathyroid hormone (PTH) 1.The key physiological
regulator of Ca 2+ metabolism 2.PTH secretion is controlled by free
Ca 2+ in plasma A.Low [Ca 2+ ] PTH secretion B.High [Ca 2+ ] PTH
secretion (Due to [Ca 2+ ] sensor in membrane of parathyroid cell)
3.Maintains [Ca 2+ ] by A.Mobilizing Ca 2+ from bone B.Promoting Ca
2+ absorption by kidney C.Stimulating the synthesis of calcitriol
1)Increases Ca 2+ absorption from intestine 2)Synergizes with PTH
in mobilizing bone Ca 2+ 4.PTH promotes phosphate excretion (Its
net effect is to Ca 2+ and phosphate in plasma) A.Vitamin D (Its
net effect is to Ca 2+ and phosphate in plasma) 5.Low intermittent
dose of PTH (1-34 Teriparatide Recombinant human PTH 1-34)
A.Stimulates osteoblast activity B.Enhance bone formation (Both
trabecular & cortical bone growth)
Slide 36
Human skeleton Hormones involved in bone metabolism &
remodeling Vitamin D 1.Main action A.Maintain plasma Ca 2+ by
increasing Ca 2+ absorption in the intestine B.Mobilizing Ca 2+
from bone & decreasing its renal excretion 2.Two sources of
vitamin D A.Dietary ergocalciferol (D 2 ) derived from ergosterol
in plants B.Cholecalciferol (D 3 ) generated in skin from
7-dehydrocholesterol by action of UV 3.Cholecalciferol (D 3 )
A.25-hydroxyvitamin D 3 (Calcifediol) in liver
B.1,25-dihydroxyvitamin D 3 (Calcitriol) in kidney 4.Ergocalciferol
(D 2 ) -calcidol (1-hydroxycholecalciferol) Calcitriol A.All can be
given orally and are well absorbed from the intestine B.Bile salts
are necessary for absorption 5.Side effects (Hypercalcemia)
A.Constipation Depression Weakness & Fatigue B.Renal stone
Renal failure if hypercalcemia persists C.Polyuria Polydipsia
Slide 37
Human skeleton 25(OH)D 3 1,25(OH) 2 D 3 1,25(OH) 2 D 3
Slide 38
Human skeleton Actions of PTH Vitamin D FGF23 on Gut Bone
Kidney PTH (Serum Ca 2+ Serum phosphate ) Intestine Ca 2+ &
phosphate absorption by increased 1,25(OH) 2 D production Kidney Ca
2+ excretion Phosphate excretion Bone High doses increase bone
resorption Low doses increase bone formation Vitamin D (Serum Ca 2+
Serum phosphate ) Intestine Ca 2+ & phosphate absorption by
increased 1,25(OH) 2 D production KidneyCa 2+ & phosphate
excretion may be decreased by 25(OH)D & 1,25(OH) 2 D Bone Ca 2+
& phosphate resorption by 1,25(OH) 2 D Bone formation may be
increased by 1,25(OH) 2 D & 24,25(OH) 2 D FGF23 (Serum
phosphate ) Intestine Ca 2+ & phosphate absorption by decreased
1,25(OH) 2 production Kidney Phosphate excretion Bone
Mineralization due to hypophosphatemia & low 1,25(OH) 2 D
levels
Slide 39
Human skeleton Hormones involved in bone metabolism &
remodeling Estrogen 1.Inhibits cytokines that recruit osteoclasts
& opposes bone-resorbing A.Ca 2+ -mobilizing action of PTH
2.HRT (Hormone replacement therapy) 3.SERMs (Selective estrogen
receptor modulators) A.Raloxifene ( Osteoblast activity &
Osteoclast activity) B.Side effects 1)Hot flash 2)Leg cramps
3)Venous thromboembolism (3x) Calcitonin 1.[Ca 2+ ] 2.Secreted by
the specialized C cells in thyroid follicles 3.Secretion is mainly
determined by [Ca 2+ ] 4.Inhibits bone resorption by inhibiting
osteoclasts 5. Ca 2+ & phosphate reabsorption in proximal
tubules of kidney
Slide 40
Human skeleton Estrogen
Slide 41
Osteoporosis Bisphosphonates Enzyme-resistant analogues of
pyrophosphate which inhibits bone mineralization Inhibiting
recruitment Promoting apoptosis of osteoclasts Bisphosphates are
given orally and are poorly absorbed About 50% accumulates at sites
of mineralization Oral bisphosphates Alendronate Risedronate
Pamidronate Ibandronate Side effects GI disturbances (not in use of
etidronate) Decreased renal function Bone pain (Occasionally)
Slide 42
Osteoporosis Strontium A divalent cation that is closely
chemically related to calcium It contains 2 atoms of stable
strontium & an organic moiety Mechanism Pre-osteoblast
proliferation & differentiation Type I collagen synthesis Bone
mineralization