Subject Index

5HT see serotonin

5HT receptors (5HTR) 117, 121, 124 6-OHDA see 6-hydroxydopamine

(6-OHDA)

acetylcholine (ACh) 83, 86–7 acetylcholine receptor (AChR) 83 aconitase 256

actin 63, 94, 101, 106

acyl CoA cholesterol transferase (ACAT) 136

adenomatosis polyposis coli (APC) 30

adenosine 50 monophosphateactivated protein kinase see AMPactivated protein kinase (AMPK)

adenovirus 18

adenylyl cyclase (AC) 211 adherens 106

adhesion molecules 179 adhesion proteins 5 adipo-insular axis 11, 30–1 adipocytes see also leptin; lipids

3T3-L1 17 adiponectin 17, 63–4

AMP-activated protein kinase (AMPK) 14, 15

autocrine e ects 15–17 circadian clock 20–1 ectopic fat 27

fatty acids feedback 14–15, 19

glucose uptake 12, 18, 140 interleukin-6 (IL-6) 141 leptin receptors (Ob-R) 15–16 MCP-1 14, 15

MLP e ect 20, 26, 30 plasminogen activator inhibitors

(PAI) 140 PPARa 17–19 STATs 46

toll-like receptors (TLR) 14, 19 transforming growth factor-b1

(TGF-b1) 141

triglycerides (TAG) 12, 14, 18, 19 visfatin secretion 178, 179

Wnt proteins 31 adipogenesis 21 adipoinsular axis 30–1

adipokines 69 see also adiponectin; apelin; ghrelin; leptin; resistin; visfatin

Alzheimer’s disease (AD) 130–42 cardiac actions 57–70, 69 circadian clock e ects 21 lifestyle e ects 176

migraine headache 116–25 neurodegeneration 178 secretion by adipose tissue 4,

11, 175 adiponectin

AdipoR 17, 28, 64 aging 175

284

adiponectin (continued) Alzheimer’s disease (AD) 139 antihypertrophic e ects 65–6 arthritis levels 5–6

autocrine e ects 15 blood plasma levels 16

cardioprotective e ects 65–6 cardiovascular disease 64–5 circadian clock e ects 21 diabetes e ect 139

fatty acids e ect 15, 139 insulin resistance 13–14, 16,

16–17, 139 lifestyle e ects 176 migraine e ect 118 obesity levels 14, 139

pancreatic b cell 27–9 production 63–4 receptors 16–17, 28, 139 relation to nitric oxide

production 5 structure 63–4, 139 TNFa expression 16–17

adiponectin receptor 1 (AdipoR1) 69 adiponectin 17, 28, 64 AMP-activated protein kinase

(AMPK) 16 insulin 118

adiponectin receptor 2 (AdipoR2) 69 adiponectin 17, 28, 64

metformin 17

peroxisome proliferator-activated receptor a (PPARa) 16,

29, 139 adipose tissue

adipoinsular axis 30–1 adipokine release 13, 32 autocrine signaling 17–21 composition 12

peroxisome proliferator-activated receptor a (PPARa) 18

ADP-ribose 179 ADP-ribosylate 181 aging

apelin 68

brain 175, 177, 178–9, 248, 254

Subject Index

central nervous system (CNS) 142 DNA repair 256

muscle proteostasis 95, 96–7 NADH oxidase 178–9 substantia nigra (SN) 248, 254 testosterone levels 81

agoutiregulated peptide (AgRP) 13 AgRP see agoutiregulated peptide

(AgRP)

AKT see protein kinases (AKT) allostasis 123

allosteric agonism 220 allosteric antagonism 220 allosteric modulators 219–21

allosteric partial antagonism 220–1 alternative medicine theories 3 Alzheimer’s disease (AD)

adipokines 130–42 astrocytosis 154–5 brain lesions 184 ceramide e ect 176

decreased glucose metabolism link 177

decreased muscle mass link 176 e ect of diet 176

FAD 130, 132

glucose metabolism 134–5 inflammation 231–2

link to diabetes 134–6 lipid metabolism 176 monocytes 177 neovascularization 183–4 pathogenesis 130, 176 plaques 5, 133 protection of blood-brain

barrier 178

reactive astrocytosis 151, 157 therapy 133–4, 175–6

amino acids (AA) burns 101 diet-derived 83, 92 disuse atrophy 98

muscle proteostasis 87–8, 89–91, 92

muscle wasting release 95–6 sarcopenia 97

286

ATP (continued) G proteins 211

mitochondrial complex I activity 248, 256–7

muscle proteostasis 93, 95 Parkinson’s disease 248, 257 PARP e ect 181, 182 proteostasis 260

PTEN phosphatase 49

reactive astrocytosis 152–3, 160 UPS role 259

visfatin e ect 178, 179 ATP-binding cassette (ABC) transporter A1 136, 242

ATP-sensitive Kþ 49 ATPase 95, 102

autocrine signaling 17–21, 191 adipokines 15, 32

insulin 22–6 leptin 58

muscle proteostasis 82–8 autophagy

muscle proteostasis 78, 84, 88, 91

Parkinson’s disease 258, 260, 269–70

axin 30

Ayurvedic medicine 240

beta adrenergic receptor (BAR) 123 bHLH-PAS domain proteins 21 biased agonists 218–19, 220

bitopic modulators 220–1 blood-brain barrier 184

adiponectin 139 astrocytes 150, 164 insulin transport 134

leptin transport 13, 15, 137 nicotinamide (Nam) 181 permeability 177, 178, 180 T-cells 231

TGF-b1 142 visfatin 140

blood-clot-dissolving factor 175 Bmal1 gene 21

box3 46

Subject Index

brain

aging 175, 177, 178–9, 248, 254 lifestyle factors 176 metabolism 121, 135–6

brain-derived growth factor (BDNF) 261

brain edema 154, 158, 159–60, 161–2, 163, 164

brain infarction 182 brain lesions 184 brain plaques

Alzheimer’s disease (AD) 232, 234 amyloidb e ect 131–3, 136, 177,

178 instability 5

interleukin-6 (IL-6) 141 therapy targets 133–4

breast cancer 105–6, 108 2-bromopalmitate 27 bulimia nervosa 118, 120 burns 80, 96, 100–1

C/EBP homologous protein-10 (CHOP) 260, 266

c-jun NH2-terminal protein kinase (JNK) 29, 62, 161, 236, 257, 263–4, 270

C-peptide 176

C-reactive protein (CRP) 13 Ca21

G protein-coupled receptors (GPCRs) 211, 213

glutamate e ect 260, 261–2 mitochondria 256–7, 262

muscle proteostasis 81, 86–7, 94–5 neurons 251

Parkinson’s disease 251–3, 256–7, 261–3

protein kinase C (PKC) 156 sepsis 100

signaling 69 cachetin see TNFa cachexia 85, 96, 101–2 cadherins 106–7 calbindin 262 calcineurin 86

Subject Index

calcium

channels 118, 120, 211 homeostasis 219 intramuscular 86 mobilizing agents 179 neural e ect 123–4 signaling 121

calcium-mobilizing agents 179 calpains 78–9, 87, 100, 262 cAMP see cyclic adenosine

monophosphate (cAMP) cancer cachexia 96, 101–2 cannabidiol (CBD) 3, 121 cannabinoid receptors 178, 222

cannabis 3, 222 see also cannabidiol (CBD); tetrahydrocannabinol (THC)

cardiac actions of adipokines 57–70 cardiomyocytes

function 59–61

leptin receptors (Ob-R) 58 resistin 67

cardiovascular disease adipokines 5 adiponectin 64 apelin 68

leptin 61

lifestyle factors 176 resistin 66–7 visfatin 68–9

cardiovascular tissues 58–9 Cas adaptor protein 108–9

caspases 78–9, 100, 183, 257, 266, 270 b-catenin 30–1, 106

caveolae 63

CBD see cannabidiol (CBD) CCR5 chemokine receptor

206–9, 221 CD38 178 CDCrel-1 259

cell cycle in Parkinson’s disease 269 cell death 179–82

cell swelling 154, 159–60, 161–2, 164 e ectors 162–3

central nervous system (CNS) adiponectin 139 astrocytes 149–51, 163–4

287

cholesterol 136 dopaminergic neurons 248 injury 151–5

insulin 133, 134 TGF-b1 141–2

ceramide 4, 5, 176, 177–8, 179 endothelial cells 177, 180 glycolysis 177

chaperones 255, 258, 259, 266, 267, 269

chemical signals 191 chemotaxis 179 chemotransduction 94 chi 3

Chinese medicine 3 cholesterol

brain metabolism 135–6

central nervous system (CNS) 136 peroxisome proliferator-activated

receptor g (PPARg) 234 transport pathway 234

cholinesterase inhibitors 176 CHOP see C/EBP homologous

protein-10 (CHOP) chromatid pairs 183 cilliary neurotrophic factor

(CNF) 83, 86 circadian clock 20–1, 32 circulatory system 179

clatherin-coated pits (CCPs) 214 Clock gene 21

CNF see cilliary neurotrophic factor (CNF)

cofilin 63 cohesin 183 collagenase 181

colony stimulating factor-1 (CSF-1) 6 connexins 107–8

contact normalization 106–10 cortical-spreading depression

(CSD) 119

corticotrophin releasing factor (CRF; CRH) 118

COX-2 see cyclooxygenase-2 (COX-2) cranial nerve system 119, 121, 122 Criegee rearrangement 180

288

CRP see C-reactive protein (CRP) Cryptochrome (Cry) gene 21

CSF-1 see colony stimulating factor-1 (CSF-1)

curcumin 239–40 cuttlefish 190 Cx43 107–8

cyclic adenosine monophosphate (cAMP)

5HTR 121, 124

adenylyl cyclase (AC) role 82, 211 arrestins e ect 214

dopamine metabolism 268 ERK pathway 264 GTPases 263

nuclear factor kappa B (NF-kB) activation 82

cyclic ADP-ribose 179 cyclins 269

cyclooxygenase-2 (COX-2) 14, 66, 162, 230, 268

cyproheptadine 125

cytokine signaling 3 (SOCS3) 13, 50 cytokines see also interleukin-6 (IL-6);

tumor necrosis factor alpha (TNFa)

adiponectin 139

adipose tissue secretion 11 anthocyanins 236

cell swelling 159–60 gallates 236

immune cell secretion 7 inflammation 30, 231, 234 levels in obesity 14

mitogen-activated protein kinases (MAPKs) 29

muscle proteostasis 83, 85–6 oxidative/nitrosative stress

(ONS) 156, 159, 163 reactive astrocytosis 151 resistin 140

sepsis 100

transforming growth factor-b1 (TGF-b1) 142

visfatin 140, 179 cytoskeleton 94–5, 106, 131

Subject Index

DAG see diacylglycerol (DAG) dehydroabietic acid 241 dementia

body mass index 136 hypertension 176 leptin 138 pellagra-induced 179 tau 131

therapy targets 133–4 deoxyribose radical cleavage 180 depression 120

DGK see diacylglycerol kinase zeta (DGKs)

diabetes mellitus (DM) 10–11

early life programming 11, 19, 21, 26, 30

etiology 5

link to Alzheimer’s disease 134–6 serotonin levels 122

Type 1 (T1DM) etiology 11

Type 2 (T2DM) etiology 11, 31, 32 Wnt proteins 31

diacylglycerol (DAG) 211, 214, 250, 252, 262–3

diacylglycerol kinase zeta (DGKs) 51–2

diet 8

Alzheimer’s disease (AD) 176 early life programming 11, 19, 21,

26, 30

e ect on migraine 120 muscle proteostasis 89–91

disease mechanisms 192, 230 disease treatment 6–8 Dishevelled (Dvl) protein 30 disuse atrophy 96, 97–9

DJ1 251, 255–6, 257, 258, 260, 265, 268, 270

DNA

damage 180–4, 182, 256

e ect of hydrogen peroxide 180 fragmentation mechanisms 180 neuronal 181

repair 179, 256 tertiary-butylhydroperoxide

(tBuOOH) model 183

Subject Index

dopamine

brain reward system 118, 119 ghrelin 119

metabolism 268–9

Parkinson’s disease 248–51, 250, 252, 268–9

dopamine D2 receptor 217, 221 dopamine D3 receptor 221 dopaminergic neuronal death 138,

247, 248–54

signaling pathways 254–70

drug receptor interaction models 1–3 drugs

design 7, 221–3 half-lives 2

receptor desensitization 6 side e ects 110, 189, 222 targets 110, 192, 223 toxicity 2, 7

Dvl see Dishevelled (Dvl) protein dyslipidemia 10, 136

early life programming 11, 19, 21, 25–6, 30

eating disorders 118, 120 ectopic fat 27, 175 electrical signaling 191

endocannabinoids 4, 5, 15, 177–8, 211 endocrine signaling 190

endocytosis mechanisms 215 endogenous ligands 3–4 endoplasmic reticulum (ER) 257,

258, 264 endorphin synthesis 8

endosomal vesicles 214 endothelial cells

adipokines 137 adiponectin 5, 137

c-jun NH2-terminal protein kinase (JNK) 62

ceramide 177, 180 gallates 236 genistein 238 MCP-1 178

NADH oxidase 178–9 piperine 238

289

endothelial nitric oxide synthase (eNOS) 5, 65–6, 177

endothelial tight junctions 178 endothelin-1 ETA receptor 60 energy metabolism 45, 177–8, 179 eNOS see endothelial nitric oxide

synthase (eNOS) enterokines 6

enzyme-linked receptors (ELRs) 191 epinephrine 80, 81–2, 100–1 epithelial-mesenchymal transition

(EMT) 107

ER see endoplasmic reticulum (ER) ER stress 29

ergosterol 243 ergot drugs 117–18

ERK see extracellular signalregulated kinase (ERK)

essential amino acids (EAA) 88, 89–90, 97

estrogen 233 exercise 6, 8

Alzheimer’s disease (AD) 176 burn recovery 101

muscle proteostasis 92–5 extracellular dehydrogenases 178 extracellular enzymes 178 extracellular matrix in muscle

proteostasis 87 extracellular plaques 177

extracellular signal-regulated kinase (ERK) 263–4

activation 29, 62, 156–7 anthocyanins 236 apoptosis 48

dopamine metabolism 268 pathway 48

reactive astrocytosis 156–7, 161

extramuscular signals 77–102

FA see fatty acids (FA)

familial hemiplegic migraine 118 fasting 17

fatty acid transport protein (FATP)-1 16

290

fatty acids (FA)

Alzheimer’s disease (AD) role 136 catabolism rate 176

diabetes role 11, 14–15 e ect on GSIS 27 feedback e ect on

adipocytes 14–15 leptin role 59 lipolysis 14 pancreatic b cell 26–7

substrates for ATP production 12 feedback 14

fenofibrate 17 Fenton reaction 248 feverfew 117

FGF see fibroblast growth factor (FGF)

fibroblast growth factor (FGF) 82–3, 84–5, 261

fibromyalgia 120–1 flunarizine 125

focal adhesion kinase (FAK) 87 forkhead transcription factors 49, 84,

183

FOXO1 see forkhead transcription factors

Foxp3 see forkhead transcription factors

frizzled (Fzd) family receptors 30, 193 Fzd see frizzled (Fzd) family receptors

G protein-coupled receptors (GPCRs) 188–224 activation 203–17

allosteric modulators 219–21 biased agonists 218–19, 220 classification 193–5, 194 conformation selectivity 203–17 crystal structures 195–6 desensitization 214

dimers 216–17

drug design 3, 221–3 endocytosis mechanisms 215

energy levels of conformations 205 epinephrine 82

GPR40 27

Subject Index

helical axis 198 identity 196–9

ligand binding 199–202, 204–6 ligand control 217–21 migraine drug target 125 mutation stabilized 204–6 orientation parameters 196–8 orthosteric binding 205, 219

sequence comparison 196–9, 197 serotonin 117

signaling 216

structure 193–217, 194, 212 testosterone e ect 81

G protein-regulated inward-rectifier K1 channels (GIRKs) 211–13

Gproteins coupling 209–14 cytosolic 218

GPCR activation 212 signal diversification 209–14

gallates 236–7

gap junctions 106, 107–8, 122 gate theory 4

GCL see glutamate cysteine ligase (GCL)

gender di erences adiponectin 16 insulin resistance 26

leptin receptors (Ob-R) 58–9 gene transcription 23, 84, 108, 181,

183, 255 genistein 237–8

GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) method 201

geraniol 242 ghrelin 21, 119 gingerol 239 ginkgo 176

GIRKs see G protein-regulated inward-rectifier K1 channels (GIRKs)

glial cell line-derived neurotrophic factor (GDNF) 261

global proteostasis 79–88 glucagon 21–2

Subject Index

glucocorticoids 80, 100, 101, 233 glucolipotoxicity 11, 29

glucose metabolism

link to Alzheimer’s disease 134–5, 177 serotonin 121

glucose-oxygen-serum-deprivation (GOSD) injury 48

glucose production 12–13 glucose-stimulated insulin secretion

(GSIS)

early life programming 26 e ect of fatty acids 26–7 insulin signaling 23, 25 leptin e ect 27–8

TNFa e ect 29

Type 2 (T2DM) diabetes 11 Wnt proteins 31

glutamate 153, 253, 254, 260–1, 264, 268

glutamate cysteine ligase (GCL) 252, 255

glutamate family of GPCRs 193 glutamate-glutamine cycle

150–1

glutamine 88, 96, 150–1 glutathione (GSH) 181, 255, 256 glycerol 12–13

glycerol 3-phosphate 12 glycerol kinase deficiency 13 glycogen metabolism 121, 122 glycogen synthase kinase 3b

(GSK3b) 30–1, 90, 135, 138 glycohydrolase 179

glycolysis 177, 181 glycoproteins 30

GPCRs see G protein-coupled receptors (GPCRs)

growth hormone (GH) 80, 93 GSH see glutathione (GSH)

GSIS see glucose-stimulated insulin secretion (GSIS)

GSK3b see glycogen synthase kinase 3b (GSK3b)

GTPase dynamin 214 GTPases 260–1, 263, 267 guggulsterone 240

291

heart disease see cardiovascular disease

helical axis 198

heparin-binding epidermal growth factor (EGF) signaling 66

herbal drugs 117–18, 230–1 HierDock procedure 200 high blood pressure

see hypertension histamine 119, 125 histone activation 183 HIV 85, 96, 156, 206, 221

HNE see 4-hydroxynonenal (HNE) holistic care 8

homology modeling 200 hormones 190

burn recovery 101 gut 6

muscle proteostasis 79–82, 93 Huntington’s disease 151, 152 hydrogen peroxide 179–82

extracellular 177 generation 177

Parkinson’s disease 251, 254, 255, 257, 264

tertiary-butylhydroperoxide (tBuOOH) model 183 6-hydroxydopamine (6-OHDA)

251, 255, 256, 257, 260, 264–5, 266, 270

4-hydroxynonenal (HNE) 256

5-hydroxytryptamine see serotonin hyperglycemia 10 hyperleptinaemia 18, 20 hyperplasia

leptin e ect 63 myostatin 85

pancreatic b cells 11, 22, 24 hypertension 5, 59 hypertrophy

adiponectin 64–6 leptin 59–61, 63

hypoglycemia 13, 17, 122, 177 hypoketonemia 17

hypothalamic physiology migraine headache 118–19

292

IAP see inhibitor of apoptosis proteins (IAP)

IDE see insulin degrading enzyme (IDE)

IGF-1 see insulin-like growth factor (IGF-1)

IkB inhibitors 158 IkB kinase

curcumin 239 genistein 237 gingerol 239 guggulsterone 240

nuclear factor kappa B (NF-kB) signaling 265–6

piperine 238 quercetin 237

IL-1 receptor (IL-1R) 27 IL-6 see interleukin-6 (IL-6)

inducible nitric oxide synthase (iNOS) adiponectin 65–6

ceramide 177 dysfunction 5 geraniol 242

nicotinamide (Nam) 181 nuclear factor kappa B

(NF-kB) 158, 162, 230, 234 Parkinson’s disease 268

inflammation adipokines 137 astrocytes 131, 150 brain 178

cascade 231–2 cytokines 30

early life programming 30 endocannabinoids 178 interleukin-6 (IL-6) 159 leptin 6, 15, 28 neutrophils 181 nicotinamide (Nam) 181 nuclear factor kappa B

(NF-kB) 158 obesity 4, 14 pancreatic b cell 29–30

Parkinson’s disease 268 phytochemicals 230–44 resistin 139–40

Subject Index

rheumatoid arthritis 5–6 sepsis 99

visfatin 140

inhibitor of apoptosis proteins (IAP) 183

iNOS see inducible nitric oxide synthase (iNOS)

inositol 1,4,5-triphosphate (IP3) 211 insulin see also glucose-stimulated

insulin secretion (GSIS) adiponectin 13, 16, 28, 139 Alzheimer’s disease (AD) 134–6 amyloidb (Ab) 133, 177 autocrine e ects 22–6

burns 101

central nervous system (CNS) 133 diabetes mellitus (DM) 11

fatty acids (FA) 12, 26–7

gene transcription regulation 23 leptin 27–8

migraine headache 123

muscle proteostasis 79–80, 83–4, 90, 91

peroxisome proliferator-activated receptor g (PPARg) 234

resistin 66 sarcopenia 97 serotonin 122 signaling 23–5 SOCS3 50 TNFa 14

insulin degrading enzyme (IDE) 133, 134, 136

insulin-like growth factor (IGF-1) 80, 81, 82, 83–4, 93, 101

insulin receptor (IR) 22–3, 69 ceramide 5, 177

isoforms 23 MLP 26

protein synthesis 84 signalling pathway 23, 25 sorting nexins (SNXs) 51 TNFa 29

visfatin 68, 178 insulin receptor substrates

(IRS) 22–4, 29, 66–7, 80, 84

Subject Index

insulin resistance 11–12 adiponectin 13–14, 16, 139 AdipoR 17

Alzheimer’s disease (AD) factor 134

ceramide 5 disuse atrophy 98

early life programming 19, 25–6, 30 interleukin-6 (IL-6) 141

IRS 19, 24 MCP-1 15, 19 obesity 136

plasminogen activator inhibitors (PAI) 141

PPARa 18 resistin 139 saturated fats 27 SOCS3 50

thiazolidinediones 234 TNFa 29

tumor necrosis factor alpha (TNFa) 14

Wnt proteins 31 integrin complexes 87

intercellular adhesion molecule 1 181 Interferon gamma (IFNg) 83 interleukin-6 (IL-6)

adiponectin 16, 139 Alzheimer’s disease (AD) 141 anthocyanins 236

cancer cachexia 101 inflammation 159, 268 link to diabetes 5 muscle proteostasis 85–6 obesity 13, 137, 141 osteoarthritis 5

reactive astrocytosis 151 relation to nitric oxide

production 5 resistin 139

rheumatoid arthritis 5–6, 231 STAT3 activation 157 stigmasterol 242 transforming growth factor-b1

(TGF-b1) 142 visfatin 140, 179

293

intracrine signaling 191 ion-channel receptors (ICRs) 191 ion channels 162–3

ion exchangers 162–3

ion transporters 161, 162–3

IP3 see inositol 1,4,5-triphosphate (IP3) IRS see insulin receptor substrates

(IRS) ischemia

apelin 68

aquaporin-4 (AQP-4) 163 astrocytes 150–1, 155, 156, 158,

159, 160, 161 cytokines 159

ion transporting systems 163 mitogen-activated protein kinases

(MAPKs) 161 nuclear factor kappa B

(NF-kB) 158, 161 oxidative/nitrosative stress

(ONS) 159 PI3K 156, 160

protein kinase C (PKC) 160 resistin 67, 139

visfatin 140

islet amyloid polypeptide (IAPP) see amylin

islets of Langerhans 11, 21–2 isoflavones 237–8

JAK-STATs pathway 28, 45–8 activation 61–2, 86

leptin receptors (Ob-R) 58, 59, 137 Janus kinase family JAK 45–6, 48,

49, 50

leptin e ects 61–2, 137–8

JNK see c-jun NH2-terminal protein kinase (JNK)

joint mobility 181 juxtacrine signaling 190–1

kinase insert domain receptor (Kdr) 109, 110

LBs see Lewy bodies (LBs)

LDL-C 5

294

LDL receptor (LDLR) 52, 135 LDLR see LDL receptor (LDLR) leptin see also adipocytes

adipose mass relationship 13, 45, 58

Alzheimer’s disease (AD) 137–9 appetite peptides 13, 137–8 artery wall defects 5

arthritis levels 6

autocrine e ects 15, 18–19, 58 cardiomyocyte function 59–61 cardiovascular actions 58–61 circadian clock e ects 21 function 45

hypertrophic e ects 59–61, 63 lifestyle e ects 176

LMB loop 123 migraine e ect 118–19 MLP e ect 20 neuropathic pain 120 obesity levels 14, 15, 58

oxygen radical formation 5 pancreatic b cell 27–9 paracrine e ects 58 Parkinson’s disease 138

peroxisome proliferator-activated receptor a (PPARa) 17–19, 20, 32

production 44, 58

resistin relationship 139–40 sciatic nerve injury 120 structure 44, 58 sympathetic nervous system

e ects 59

leptin receptors (Ob-R) 15 Alzheimer’s disease (AD) 137 cardiovascular tissues 58–9 interactions 50–2

isoforms 45, 58 levels in obesity 16

signaling 15, 45–50, 47, 61–3 leucine 88, 89, 91

leucine-rich repeat kinase 2 (LRRK2) 260, 267

Lewy bodies (LBs) 251, 256, 258, 260, 269

Subject Index

lifestyle e ects 6, 7–8, 175–6, 184 ligands see also adipokines; cytokines

endogenous 2

GPCR binding 199–202, 204–6, 217–21

receptor binding 1–3 linear model 1–2

lipid phosphatase PTEN 49 lipid rafts 136, 138

lipids see also adipocytes; ceramide; endocannabinoids

adiponectin 13

brain accumulation 176, 178 disorders 135–6

GPCRs 199, 200 homeostasis 11, 234 insulin 11, 18 liberation 2

metabolism 51, 123, 135, 137, 176 obesity 4

peroxidation 256 phospholipase mechanisms 2 PI3K/AKT signaling 265 toxic 4, 6, 176

lipocalins 51 lipolysis

circadian clock e ects 20 insulin regulation 123

lipoprotein lipase (LPL) 12 lipotoxicity 5 liver-X-receptor (LXR)

agonists 242–3

NF-kB regulation 234–5 phytochemicals 234

LMB loop 123

LPL see lipoprotein lipase (LPL) LRRK2 see leucine-rich repeat kinase

2 (LRRK2)

LXR see liver-X-receptor (LXR) lymphocytes 178

lysosomes 78–9, 84, 88, 132 autophagy 260, 269

macrophages adipokines 4, 119

cytokines 13, 30, 83, 164, 231, 234

Subject Index

diabetes mellitus (DM) 19, 119 fatty acids (FA) 15

foam cells 5, 234 glutamine 96 interleukin-6 (IL-6) 13, 86 leptin 6

LXRs 231

MCP-1 13–14, 15, 19 muscle communication 83 NADH oxidase 178 NADPH oxidase (NOX) 178 obesity 4, 13, 119

PPARa 18–19 PPARg 231 resistin 6

sciatic nerve injury 120 TNFa 13–14

visfatin 179

MAO see monoamine oxidase (MAO) MAPKs see mitogen-activated

protein kinases (MAPKs) Maraviroc 206

Maternal Low Protein (MLP) 19–20, 26, 30

maternal nutrition 11, 19, 21, 26, 30 matrix model 2–3

MCP-1 see monocyte chemoattractant protein 1 (MCP-1)

MechanoGrowth Factor (MGF) 82 mechanotransduction 94 membrane proteins

APP 177 classes 191–2

signaling 189, 191–2 MembStruk method 200 metabolic syndrome 175

Apo D 51

endocannabinoids increase 178 fatty acids increase 12 lipolysis increase 12

plasminogen activator inhibitors (PAI) 141

metabolism

Alzheimer’s disease (AD) 134–6 autocrine signaling 19–20 dysfunction 134–6

295

fasting 17

migraine 120, 121, 124 Parkinson’s disease 248

metalloproteases 5, 132, 133, 136 metformin 17 1-methyl-4-phenylpyridinium

(MPP1) 248, 251, 254–6, 260, 263, 264, 266

methyl-beta-cyclodextrin 63 methysergide 117

MGF see MechanoGrowth Factor (MGF)

microadenomas 105–6 migraine headache 117–25

pathophysiology 118–19 mitochondria 249, 256–7

burns 100

c-jun NH2-terminal protein kinase (JNK) 264

disuse atrophy 99 DJ1 255

DNA damage 181, 182 migraine headache 118 monoamine oxidase (MAO) 251 muscle proteostasis 88, 98 nicotinamide (Nam) 179

p53 162

PINK1 255, 262, 267 reactive astrocytosis 151 sepsis 100

visfatin 69

mitochondrial complex I activity 248, 256

mitochondrial membrane potential (MMP) 162, 242, 249, 256–7 mitogen-activated protein kinases

(MAPKs)

Alzheimer’s disease (AD) 138 cardiomyocytes 59

connexin phosphorylation 108 cytokines 29

GTPases e ect 263 muscle proteostasis 84

p38 59–60, 62–3, 156, 161, 213, 218, 263–5

p44/42 60

Subject Index

neurons 152 acetylcholine 86 aging 175

Apo D 51

ApoE 135

astrocyte function 121, 122, 123, 150 Ca21 251

DNA damage 181 glutamate 150 glutamine 150 glutathione (GSH) 255 hypothalamic 13 interleukin-6 (IL-6) 141 leptin 13, 48, 49, 51, 52 NADH 179 neurotrophins 83 oligomers 131

plasminogen activator inhibitors (PAI) 141

TGF-b1 142 visfatin 140

neuropathic pain 119–21 neuropeptide Y (NPY) 13 neurotransmitter synthesis 181 neurotrophins 83, 86, 261 neutrophils

inflammation 5, 181 penetration of blood-brain

barrier 177

NF-kB see nuclear factor kappa B (NF-kB)

NGF see nerve growth factor (NGF) niacin 179

nicotinamide mononucleotide (NMN) 140, 178, 179

nicotinamide (Nam) 140, 178, 179, 181, 183

nicotinamide phosphoribosyl transferase (NAD) 140, 178–9, 181

nicotinic acid ADP (NaADP) 179 nitric oxide synthase 177, 254, 262 NMN see nicotinamide

mononucleotide (NMN) nocioception 4, 121 non-chemical signals 191 normal aging 177

297

NOX see NADPH oxidase (NOX) NPY see neuropeptide Y (NPY) NSAIDs 119

nuclear factor kappa B (NF-kB) 265–6

activation 14–15, 161–2 bacteria activation 232 cancer cachexia 102 function 232 inflammation 230, 232–3 inhibitors 233–43

LXRs 242

muscle proteostasis 85, 94 pancreatic b cells 29 Parkinson’s disease 265–6 peroxisome proliferator-activated

receptor g (PPARg) 241–2 reactive astrocytosis 158, 161–2 signal transduction pathway 233,

265–6 structure 232

nuclear swelling 182 nutrition

Alzheimer’s disease (AD) 176 early life programming 11, 19, 21,

26, 30

e ect on migraine 120 muscle proteostasis 89–91

Ob-R see leptin receptors (Ob-R) obesity

Alzheimer’s disease link 136, 176 circadian clock e ects 20–1, 32 decrease in adiponectin 5 diabetes link 11–12

early life programming 11, 19, 21, 25–6, 30

e ect of MLP 19–20

e ect on signal transduction networks 4–5

hypertrophy 60 increase in adipokines 4 leptin resistance 13 pancreatic b cell

inflammation 29–30 shift work link 20

298

oleate 26, 28 oncomirs 109

ONS see oxidative/nitrosative stress (ONS)

opioids 6

OPM (Orientation of Proteins in Membrane) database 196

orexins 119

orientation parameters 196–8 orthosteric binding 205, 219, 220–1 osteoarthritis 5

osteoclasts 6 osteokines 6

oxidative/nitrosative stress (ONS) 155–6, 159, 160, 254–7

oxLDL 233, 234

oxygen radicals 177, 179–82 oxysterols 234

p38 pathway 59–60, 62–3, 69, 257, 263–5, 268, 270

p53 162, 181, 183, 266

p75 neurotrophin receptor (p75NTR) 177, 261

p75NTR see p75 neurotrophin receptor (p75NTR)

p85 regulatory subunit 25, 26

p110 protein 25, 26 Pael-R 251, 259, 260 palmitate 26, 28–9

PAMs see positive allosteric modulators (PAMs)

pancreas islets of Langerhans 11, 21–2 pancreatic a cells 21–2

pancreatic b cells 11, 21–32, 90 paracrine signaling 190

leptin 58

muscle proteostasis 82–8 Paraquat 248, 254–5, 260

parkin 255–6, 257, 258, 259, 260, 265, 266

Parkinson’s disease 247–71 Alzheimer’s disease link 176 brain lesions 184

dopamine D2 receptor agonists 221

Subject Index

etiology 247–8, 256 ghrelin 119 inflammation 268 leptin 138

Lewy bodies (LBs) 251 mitochondrial complex I

activity 248 neovascularization 183–4 pathological events 249–50, 252 reactive astrocytosis 151

PARP see poly(ADP-ribose) polymerase (PARP)

PBEF see visfatin

PDCD2 see programmed cell death-2 (PDCD2) protein

PDE see phosphodisterases (PDEs) Pdpn 109–10

pellagra-induced dementia 179 pentose phosphate 181 peptides 13

Period (Per) gene 21 PERK 29, 266 peroxide migration 180

peroxisome proliferator-activated receptor a (PPARa) 13 adipocyte glucose uptake 18 adiponectin 16, 66, 139 AdipoR2 16, 29, 139 deficiency 17–19

fatty acids catabolism 234 leptin 17–19, 20, 32

peroxisome proliferator-activated receptor g (PPARg) 12 adipocyte di erentiation 233–4 adiponectin 17, 64, 66, 139 agonists 241–2

cholesterol 234 function 233–4 insulin sensitizing 234 leptin 18, 46, 139

NF-kB regulation 233–4 phytochemicals 231 STAT1 signaling 46

peroxynitrite radicals 177, 179–80

phenylalanine 82, 88, 89

Subject Index

phosphatidylinositide 3-kinase (PI3K) see PI3K

phosphatidylinositol 3-kinases (PI3K) see PI3K

phosphatidylinositol 3,4,5- triphosphate (PI3P) 49

phosphodisterases (PDEs) 124 phosphoinositide 3-kinase (PI3K)

see PI3K 3-phosphoinositide-dependent

protein kinase1 (PDK1) 49 phosphoinositide-specific

phospholipase C (PI-PLC) 211 phospholipase C (PLC) 81, 86, 211,

250, 252, 263 phospholipase D (PLD1) 95

phospholipase mechanisms 2, 95 phospholipids 135, 262 phosphorylation 179–80 phosphotyrosine residues 46, 47, 48,

49, 50 phytanic acid 241

phytochemical inhibitors 235–40 phytochemicals 230–44

PI-PLC see phosphoinositide-specific phospholipase C (PI-PLC)

PI3K

amino acids e ect 90 astrocytes 156, 160 classes 24–5 glucocorticoid e ect 80 GTPases e ect 263

insulin e ect 25, 26, 84, 135 leptin signaling 15, 49 MAPK e ect 264 neurotrophins 86

Parkinson’s disease 250, 252, 265 signaling pathway 49, 69, 265 visfatin e ect 69

PI3K/AKT signaling 49, 265 apoptosis 270

insulin 135 MAPK e ect 264 neurotrophins 86 resistin e ect 67 sepsis 100

299

PINK1 255–6, 257, 260, 262, 265, 267 piperine 238, 239

PKA see protein kinase A (PKA) PKC see protein kinase C (PKC) PKG see protein kinase G (PKG) placebo e ect 4

plaques

Alzheimer’s disease (AD) 234 amyloidb e ect 131–3, 136, 177, 178 atherosclerosis 234

instability 5 interleukin-6 (IL-6) 141 therapy targets 133–4

plasma membranes acetylcholine 86 ATP 257

C-terminal cleavage 131 epinephrine 82 essential amino acids 88

fibroblast growth factor (FGF) 84 G protein-coupled receptors

(GPCRs) 81, 82, 192, 203, 213, 214

GTPases 214 insulin receptor 84

integrin complexes 87 ion-channel receptors (ICRs) 191 NADH oxidase 178 neurotrophins 86

PI3K 265

protein kinase C (PKC) 156, 263 proteins 189, 190, 191

secretases 131–2

stretch-activated channels (SAC) 94 testosterone 81

plasminogen activator 178 plasminogen activator inhibitors

(PAI) 140–1, 178

PLC see phospholipase C (PLC) PLD1 see phospholipase D (PLD1) pleiotropic receptors 204, 209 poly(ADP-ribose) 181 poly(ADP-ribose) polymerase

(PARP) 179, 180–1, 182, 183, 256 poly(ADP-ribosylate) 181 pomegranate 236

300

positive allosteric modulators (PAMs) 220

positive cofactor 1 181

PP2A see protein phosphatase type 2A

PPARa see peroxisome proliferatoractivated receptor a (PPARa)

PPARg see peroxisome proliferatoractivated receptor g (PPARg)

pre-B cell colony enhancing factor see visfatin

preadipocytes 20

programmed cell death-2 (PDCD2) protein 259

prostaglandin (PG) synthesis 66 proteasome 78

protein kinase A (PKA) beta adrenergic receptor

(BAR) 123

dopamine metabolism 268 fatty acid feedback 14 muscles 82

Parkinson’s disease 250, 252 protein kinase B (Akt)

muscle proteostasis 80, 84, 85, 90–1 Parkinson’s disease 250, 252, 257,

265

protein kinase C (PKC) 156, 159, 160, 163

apelin 68

Ca21 86–7, 211, 262–3 neurotrophins 86 Parkinson’s disease 250, 252 signaling 69

protein kinase G (PKG) 160 protein kinases (AKT) see also

mitogen-activated protein kinases (MAPKs)

apelin e ect 68 cancer 108 desensitization 214 matrix model 2 muscle proteostasis 87 Rho 63

signaling 47, 49, 69, 135 stimulation 62–3

Subject Index

protein phosphatase type 2A 179–80 protein tyrosine phosphatase 1B

(PTP1B) 62

proteostasis 258–60 see also muscle proteostasis

Prozac 222

PTEN phosphatase 49 purines 157

quercetin 237

rapamycin complex 1 (mTORc1) 84, 88, 90–1, 93–4, 97

reactive astrocytosis 151–3, 155–8, 159, 164

reactive oxygen species (ROS) muscle proteostasis 94–5, 99 Parkinson’s disease 248, 249–50,

252, 255, 256, 257, 262 sepsis 100

receptor activator of NF-kB (RANK) 232

receptor of G protein signaling (RGS) 6

receptors 1–3 see also specific receptors

reperfusion 184 Rescriptor 222 resistin

Alzheimer’s disease (AD) 139–40 cardiac actions 67 cardiovascular actions 66–7 glucose transport 67

leptin relationship 139–40 production 66–7, 139 relation to nitric oxide

production 5 structure 66–7, 139 vasodilation 5

Rev-Erba transcription factor 21 RGS see receptor of G protein

signaling (RGS) rheumatoid arthritis 5–6, 231 RhoA/ROCK system 63

Rhodopsin family of GPCRs 193 rimonabant 222

Subject Index

RNA polymerase II 181 RNA polymerase III 181 rosiglitazone 28–9 Rotenone 248, 254–5, 256

sarcopenia 81, 96–7, 98 saturated fats 27 sca olding proteins 30 schizophrenia 118 sciatic nerve injury 120

secretases 131–2, 133, 136 Secretin/Adhesion family of

GPCRs 193

selective dopaminergic neuronal death 248–54

signaling pathways 254–70 sepsis 80, 87, 96, 99–100, 101 serine phosphorylation 29, 90, 156,

157, 160

serine/threonine kinases 157, 160, 191, 262, 264, 265, 269 see also glycogen synthase kinase 3b (GSK3b); protein kinase C (PKC)

serotonin 117–18 astrocyte role 121

metabolic e ects 121, 122 shift work link to obesity 20 signal diversification 189, 209–14 signal modulation 189, 230–44

Signal Transducers and Activators of Transcription proteins

(STATs) 46–8 see also transcription 3 (STAT3) leptin signaling 62 STAT5 28

signaling cascades 190–1, 263–6 signaling proteins 188 signaling types 190–1 b-sitosterol 243

sleep mechanisms 119, 120, 121 SN see substantia nigra (SN) SNX see sorting nexins (SNXs) SOCS3 see cytokine signaling 3

(SOCS3)

soluble proteins 190 sorting nexins (SNXs) 51

301

spatio-temporal separation of signaling 190–1

sphingomyelin catabolism 176 sphingomyelinase 177 spirituality 8

Src 107, 108–9

STAT3 see transcription 3 (STAT3) STATs see Signal Transducers and

Activators of Transcription proteins (STATs)

stearate 26 stigmasterol 242

stretch-activated channels (SAC) 94 stroke see also brain infarction

cell swelling 154 etiology 176 immediate care 175 inflammation 181

oxidative/nitrosative stress (ONS) 155–6

reactive astrocytosis 151 recovery 183

toxic lifestyle e ects 184 Structure-Activity- Relationship

(SAR) data 200

substantia nigra (SN) 247, 248, 251, 254, 256, 260, 267

superoxide 178–9

superoxide dismutases 248, 255 superoxide radicals 177, 254 swelling e ectors 162–3 sympathetic nervous system 15, 123 synapses 177

synovitis 231

a-Synuclein 258, 259, 260, 262, 268–9

T-cell-specific transcription factor/ lymphoid enhancer binding factor 1 (TCF/LEF1) family binding proteins 31

T-cells 231

T1DM see diabetes mellitus (DM) T2DM see diabetes mellitus (DM) TAG see triglycerides (TAG) tankyrase 181

taranabant 222

302

targeted drug design 221–3 Taste2 family of GPCRs 193 tau

Alzheimer’s disease (AD) 131–3, 232 lipid disorders 135

therapy target 134 tBuOOH see tertiary-

butylhydroperoxide (tBuOOH) TCF/LEF1 see T-cell-specific

transcription factor/lymphoid enhancer binding factor 1 (TCF/ LEF1) family binding proteins

terpinoids 241–2 tertiary-butylhydroperoxide

(tBuOOH) 183 testosterone 81, 93, 101

tetrahydrocannabinol (THC) 3 TGF-b1 see transforming growth

factor-b1 (TGF-b1)

THC see tetrahydrocannabinol (THC) thiazolidinediones 234–5 thioredoxins (Trx) 257

threonine phosphorylation 156, 157, 160

thrombosis 176

thyroid hormone (TH) 80–1, 100–1, 268

titin 94

TLR see toll-like receptors (TLR) Tmem163 109, 110

TNFa see tumor necrosis factor alpha (TNFa)

TNFR see tumor necrosis factor receptor (TNFR)

toll-like receptors (TLR) 14, 27, 232 tonabersat 122

toxic lifestyles 6, 7–8, 175–6, 184 transcription 3 (STAT3)

activation 46, 157–8, 161 e ect of SOCS3 50 resistin 139

transforming growth factor-b1 (TGF-b1) 141–2, 156

transient receptor potential cation channel vanilloid 1 (TRPV1) 178

transmembrane enzymes 177

Subject Index

transmembrane (TM) signal transduction 189

trigeminal nerve 119, 121, 122 triglycerides (TAG)

accumulation 12, 176 leptin 15–16, 18 lipolysis 14

peroxisome proliferator-activated receptor g (PPARg) 234

transport 176 uptake 176

TrkA see tropomyosin related kinase A (TrkA)

tropomyosin related kinase A (TrkA) 177

TRPV1 see transient receptor potential cation channel vanilloid 1 (TRPV1)

tumor necrosis factor alpha (TNFa) adhesion molecule secretion 179 adiponectin 16–17

anthocyanins 236 cancer cachexia 101 CSF-1 production 6 fatty acids 15 genistein 237–8

insulin resistance 14, 29 levels in obesity 13–14, 15 lifestyle e ects 176 lymphocyte suppression 15 muscle proteostasis 85–6 pancreatic b cell 29 piperine 238

quercetin 237

relation to nitric oxide production 5 sepsis 100

visfatin 179

tumor necrosis factor receptor (TNFR) 29, 83, 85, 183, 232, 268

tumor promoters 108, 109–10 tumor suppressors 106–7, 108–9, 181 tyrosine kinases see also enzyme-

linked receptors (ELRs); insulin receptor (IR)

arrestins 216 insulin 22, 24

Subject Index

neurotrophins 86, 261 sorting nexins (SNXs) 51

tyrosine phosphorylation 24, 29, 46, 62, 106

ubiquitin 82, 251, 255, 263, 265, 266 ubiquitin proteasome system

(UPS) 78, 257, 258–60 cachexia 85, 101–2 disuse atrophy 99 glucocorticoids e ect 80 insulin/IGF-1 e ect 84 myostatin 85

NF-kB e ect 85, 232 unfolded protein response

(UPR) 257, 266 unsaturated fats 27

UPR see unfolded protein response (UPR)

UPS see ubiquitin proteasome system (UPS)

vacuole formation 182 Vadilex 222

Vegfr2 109, 110

ventral tegmental area (VTA) 251

303

visceral fat 175 visfatin 68–9

Alzheimer’s disease (AD) 140 arthritis 6

blood-brain barrier 179 circadian clock e ects 21 function 178–9 inflammation 140

insulin mimetic activity 178 link to diabetes 5

oxygen radical formation 5, 179 structure 140

vasodilation 5

VTA see ventral tegmental area (VTA)

WHIMS trial 176

white adipose tissue 12, 18, 32 Wnt proteins 30–1, 193

xanthine oxidoreductase 178

yang 3 yin 3

zinc-metallopeptidase 133