Slide 1

Pharmacotherapy of obesity & osteoporosis

Slide 2

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

Slide 13

Body weight regulation Mechanism (Central) Leptin 1. -MSH NPY AgRP 2. 3.Adipose-derived satiety hormone Inhibits neurons co-expressing orexigenic hormones NPY & AgRP Stimulates neurons co-expressing anorexigenic hormones -MSH & CART

Slide 14

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

Slide 43

Osteoporosis Strontium

Slide 44

Osteoporosis