SESSIONE I: RELATORI. Ghrelin: from oroxigenic signal to metabolic master regulator?

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1 SESSIONE I: RELATORI Ghrelin: from oroxigenic signl to metbolic mster regultor? Prof. Rocco Brzzoni Professore ssocito di Medicin Intern Università degli Studi di Trieste

2 Ghrelin: d segnle oressizznte regoltore del metbolismo intermedio Rocco Brzzoni Dept of Medicl, Surgicl nd Helth Sciences University of Trieste - Itly

3 OBESITY METABOLIC SYNDROME Nutritionl Metbolic Vsculr Hormonl Neurodegenertive DISEASES

4 Ghrelin-O-Acyl Trnsferse (GOAT) Octnote + Ghrelin A-Ghrelin (5%) Appetite + Nutrients + Weight Ft

5 Low totl ghrelin in humn obesity Tschop et l, Dibetes 2001

6 Ghrelin-O-Acyl Trnsferse (GOAT) Octnote + Ghrelin A-Ghrelin (5%) Leptin Brzzoni et l, Gstroenterology 2003 Insulin Sd et l, JCEM 2002 Appetite + Nutrients + Weight Ft

7 A-Ghrelin Appetite Skeletl Muscle Mitochondri Oxidtive Metbolism Insulin Signlling Immune Inflmmtion

8 A-Ghrelin Appetite Skeletl Muscle Mitochondri Oxidtive Metbolism Insulin Signlling Imm Syst Inflmmtion A-Ghrelin: FASTING - CALORIE RESTRICTION hormone?

9 A-Ghrelin Appetite Liver Glucose Production Insulin Signlling Pncres Insulin Blood Glucose Whole-Body Insulin Resistnce A-Ghrelin: FASTING - CALORIE RESTRICTION hormone?

10 Chronic Kidney Disese Wynne et l, J Am Soc Nephrol 2005 Ashby et l, Kidney Int 2009

11 OBESITY nd METABOLIC SYNDROME: ltered PLASMA ghrelin profile nd ssocitions with insulin resistnce AG UnAG Brzzoni et l, JCEM 2007 UnAG UnAG AG/UnAG

12 Is UnAG n independent (nd potentilly beneficil) hormone? UnAG

13 Ox Stress Inflmmtion Insulin Resistnce

14 Ox Stress Inflmmtion UnAG Insulin Resistnce

15 Ox Stress Inflmmtion UnAG Insulin Resistnce

16 Ox Stress Inflmmtion UnAG Insulin Resistnce

17 OBESITY? Ox Stress Inflmmtion Insulin Resistnce

18 Geneticlly-induced chronic UnAG elevtion prevents obesity-ssocited insulin resistnce nd hyperglycemi Gortn Cppellri et l, Dibetes 2016

19 Are UnAG ctivities direct nd independent of AG?

20 Myotubes in vitro: AG vs UnAG Gortn Cppellri et l, Dibetes 2016

21 CHRONIC Disese Ox Stress Inflmmtion Insulin Resistnce WASTING

22 Is UnAG potentil tretment for chronic disese-ssocited muscle metbolic ltertions?

23 nmol/mg protein/min Experimentl CKD ROS genertion nd redox stte Gstrocnemius Mitochondril H 2 O 2 Production b b c b b b Shm Nx Nx-UnAG 0 GMS S GM PCM Gstrocnemius GSSG:Totl Glutthione 0.08 b GSSG/GSH+GSSG Gortn Cppellri et l, FASEB Journl under first revision

24 Experimentl CKD Inflmmtion Cytokines pg/mg protein b b b b b Shm Nx Nx-UnAG 0 IL-1lph IL-1bet TNFlph IL-6 IL-10 Gortn Cppellri et l, FASEB Journl under first revision

25 Experimentl CKD Insulin signlling nd MUSCLE MASS Insulin signlling p/t protein (U/pg) b b b b b 0 IR IRS-1 AKT GSK3b PRAS-40 P70S6K (0.1x) (20x) Muscle weight (g) Muscle weight b Shm Nx Nx-UnAG Gortn Cppellri et l, FASEB Journl under first revision 0

26 Wht re the mechnisms of muscle UnAG ctivities?

27 AUTOPHAGY: complex ctbolic process contributing to disposl of DAMAGED tissue orgnelles (MITOCHONDRIA) AUTOPHAGY EXCESS DEATH DEFECT DAMAGE ACCUMULATION DYSFUNCTION Friedrich et l, Physiol Rev 2015

28 UnAG ntioxidnt nd insulin-sensitizing effects re medited by AUTOPHAGY in myotubes Gortn Cppellri et l, Dibetes 2016

29 UnAG ntioxidnt nd insulin-sensitizing effects re medited by AUTOPHAGY in myotubes In vitro uremic model Gortn Cppellri et l, FASEB Journl under first revision

30 Autophgy ctivtion in Skeletl Muscle - CKD Shm Nx Nx-UnAG 60 c % LC3 positive fibers b 0 Shm Nx Nx-UnAG LC3 (Alex Fluor 594) Lectin - FITC Nuclei - DAPI Gortn Cppellri et l, FASEB Journl under first revision

31 OBESITY CKD

32 UnAG HUMAN RELEVANCE?

33 Bseline plsm UnAG predicts insulin sensitivity (n=250; generl popultion cohort; 5-y follow-up) * ** Brzzoni et l, Clin Nutr 2016

34 Chnges in plsm ghrelin profile predict chnges in insulin sensitivity AG UnAG (5-y follow-up) R=-0,19; P=0,01 Log HOMA Delt Log HOMA Adj: Delt BMI R=0,12; P=0,2 Log AG A/UnAG Delt Log DG Delt Log HOMA R=0,17; P=0,03 Brzzoni et l, Clin Nutr 2016 Delt Log A/DG

35 THERAPEUTIC PERSPECTIVE Obesity nd Metbolic Syndrome AG DG Ghrelin-O-Acyl Trnsferse (GOAT) Ghrelin A-Ghrelin UnA-Ghrelin

36 THERAPEUTIC PERSPECTIVE Chronic Disese-Induced Mlnutrition UnAG CHRONIC Disese AG + APPETITE Ox Stress Insulin Resistnce Mitochondril DYSFUNCTION Inflmmtion WASTING

37 THERAPEUTIC PERSPECTIVE Neurodegenertive Disese-Induced Mlnutrition Neurodeg Disese UnA G AG + APPETITE Ox Stress Insulin Resistnce Mitochondril DYSFUNCTION Inflmmtion WASTING

38 THERAPEUTIC PERSPECTIVE Neurodegenertive Disese-Pthophysiology AG UnAG? Neuroprotection Synptic function Neurodeg Disese Ox Stress Inflmmtion Mitochondril DYSFUNCTION AD ALS Prkinson

39 THERAPEUTIC PERSPECTIVE Neurodegenertive Disese - Pthophysiology J Neurosci 2016 Neurobiol Dis 2014

40 Summry -Ghrelin is gstric orexigenic hormone circulting in cylted nd uncylted forms (UnAG) -AG hs orexigenic effects nd my enhnce muscle mitochondril function with potentil ntictbolic effects -UnAG hs independent metbolic effects tht include reduction of muscle oxidtive stress, inflmmtion nd insulin resistnce -UnAG my normlize metbolic ltertions cusing muscle wsting nd hyperglycemi in chronic disese or in diet-induced obesity -UnAG ctivities pper to be medited by utophgy nd removl of dysfunctionl orgnelles (mitochondri)

41 These combined observtions indicte potentil for combined utiliztion of UnAG (direct dministrtion, downregultion of ghrelin cylting systems) nd-or AG s therpeutic strtegies for chronic disese-relted mlnutrition s well s obesity-ssocited neurodegenertive complictions

42 Trieste tem: G Gortn A Semolic P Vinci M. Znetti Acknowledgements Collbortions: D. Mrks M. Gicc A. Grzini