Cardiovascular Biology of the Leptin/Melanocortin System

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1 Cardiovascular Biology of the Leptin/Melanocortin System Alexandre A. da Silva, Ph.D., FAHA Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, MS p<0.05 compared to vehicle

2 Safety Pharmacology Society Meeting Disclosure of Relationships Over the past 12 months No relationships to disclose

3 Rio de Janeiro (early 1990 s) Rio de Janeiro (2016)?

4 Obesity is a major cause of human essential hypertension Insulin Resistance Dyslipidemia NIDDM Obesity Hypertension (65-75%) Atherosclerosis Kidney Disease

5 SBP (mmhg) Body Weight (kg) Mean Arterial Pressure (mmhg) Weight gain is positively associated with increases in arterial pressure HIGH FAT N = 22, BMI (kg/m 2 ) C Time (weeks) Jones D et al. J Hypertens 12: , 1994 Hall JE et al. Hypertension 23:381-94, 1994

6 Mechanisms of Obesity-Induced Hypertension Intrarenal abnormalities (including physical compression of the kidneys by surrounding visceral fat) Activation of the renin-angiotensin-aldosterone-system Sympathetic nervous system activation

7 D Mean Arterial Pressure (mmhg) Cumulative Na+ Retention (mmol) Mean Arterial Pressure (mmhg) Chronic adrenergic receptor blockade and bilateral renal denervation markedly blunt obesity-induced hypertension 20 High Fat Diet Control Denervated High Fat Diet 15 Control a + b Blockade C Time (weeks) Hall JE et al. Hypertension 23:381-94, Control Denervated Time (weeks) Kassab S et al. Hypertension 25:893-97, 1995

8 a + b adrenergic blockade decreases ambulatory mean arterial pressure more in obese than in lean hypertensive patients Mean Arterial Pressure (mmhg) p=.02 Obese Lean 90 Control a & b Block Wooford, M et al. Am J Hypertens 14:694-98, 1991

9 Potential mechanisms leading to increased sympathetic activation in obesity Davy KP and Hall JE. Am J Physiol Regul Integr Comp Physiol 286:R803-13, 2004

10 HR (bpm) MAP (mmhg) Food Intake (g/day) Chronic leptin infusion, at rates that mimic leptin levels in severe obesity, raises BP and HR in lean rats Leptin (µg/kg/min) * * * * Plasma Leptin = 91 ng/ml 30 Leptin (µg/kg/min) * * * * * * * 20 * * * * * * * * 10 * * ** * Days Days Shek EW et al. Hypertension 31:409-14, 1998

11 D MAP (mmhg) D HR (bpm) Chronic a + b adrenergic receptor blockade abolished the rise in BP and HR caused by leptin infusion Leptin (µg/kg/min) Control a-ß blockade Carlyle M et al. Hypertension 39: , 2002 Days

12 Inhibition of nitric oxide synthesis with L-NAME enhances leptin-induced hypertension and tachycardia Kuo JJ et al. Hypertension 37:670-76, 2001

13 Impaired nitric oxide formation amplifies the hypertensive effects of leptin Obesity Leptin Endothelial Dysfunction x Sympathetic Activity Nitric Oxide + Blood Pressure

14 Leptin deficient mice are severely obese and exhibit many features of metabolic syndrome WT Ob -/- 3.0 * * WT ob-/- mice Epididymal Fat (g) 0.0 Retroperitoneal Fat (g) 250 * * do Carmo JM et al. Hypertension, 52: e104, Glucose (mg/dl) Insulin (mu/ml)

15 MAP (mmhg) Telemetry- 5 days average Despite severe obesity leptin deficient mice do not have elevated BP WT Ob -/ WT Ob -/- do Carmo JM, da Silva AA and Hall JE. Hypertension, 52: e104, 2008

16 Humans with leptin deficiency are markedly obese Farooqi & O Rahilly, NEJM 2004.

17 Humans with leptin gene mutations are not hypertensive despite early onset obesity and metabolic syndrome Results: 4 patients with homozygous missense mutations of the leptin gene all had early onset morbid obesity and severe insulin resistance, hyperinsulinemia dyslipidemia decreased sympathetic activity, postural hypotension decreased renin-angiotensin-aldosterone system response to upright posture no hypertension Note: All subjects studied were young, with early onset obesity. Ozata M et al. J Clin Endocrinol Metab 84: , 1999

18 Leptin appears to be an important link between obesity, sympathetic activation and hypertension in humans as well as in rodents.

19 Potential brain mechanisms by which leptin regulates appetite and sympathetic activity: role of the melanocortin system Paraventricular nucleus MC4-R NPY AGRP POMC + + a-msh + LEPR Arcuate nucleus MC4-R a-msh Leptin Lateral Hypothalamic area Nucleus tractus Solitarius Appetite - Sympathetic activity + Adipose Tissue

20 MC4R deficient mice are obese and exhibit many features of metabolic syndrome WT mouse MC4R-/- mouse * * Epididymal Fat (g) * Retroperitoneal Fat (g) * Wild Type mice MC4R (+/-) mice MC4R (-/-) mice Tallam LS et al. Hypertension 46:326-32, Leptin (ng/ml) 0 Insulin (mu/ml)

21 MAP (mmhg) MAP (mm Hg) MC4R deficient mice are not hypertensive and are resistant to the hypertensive effects of leptin Wild Type mice, N = 7 MC4R (+/-) mice, N = 6 MC4R (-/-) mice, N = Leptin 2 mg/kg/min MC4R (-/-) Wild Type WT MC4R +/- MC4R-/- 100 C1 C2 C3 E1 E2 E3 E4 E5 E6 E7 Days L Tallam et al. Hypertension 46: , 2005.

22 Humans with MC4R deficiency exhibit marked early onset obesity, but have normal to low BP and reduced SNS activity most common monogenic form of obesity Appetite Insulin resistance Insulin Leptin Dyslipidemia Blood pressure Sympathetic Activity 9-year old boy with MC4-R Mutation 16-year old brother with normal MC4-R genotype Greenfield JR et al. N Engl J Med. 360:44-52, 2009

23 BP, 24-hr urinary NE excretion and hypertension prevalence are lower in obese MC4R deficient subjects than obese controls Greenfield JR et al. N Engl J Med. 360:44-52, 2009

24 Activation of the CNS melanocortin system (e.g., activation of MC4R) appears to be necessary for obesity and hyperleptinemia to raise SNA and BP.

25 Blockade of MC4R causes a greater reduction in BP in SHRs compared to Wistar rats da Silva AA et al. Hypertension 51:884-90, 2008.

26 Potential brain mechanisms by which leptin regulates appetite and sympathetic activity: role of the melanocortin system Paraventricular nucleus MC4-R NPY AGRP POMC + + a-msh + LEPR Arcuate nucleus MC4-R a-msh Leptin Lateral Hypothalamic area Nucleus tractus Solitarius Appetite - Sympathetic activity + Adipose Tissue

27 Generation of mice with selective leptin receptor deletion in proopiomelanocortin (POMC) neurons 5 exon 4 + Cre exon Floxed lepr gene - Cre defective gene Transcription normal mrna LepR flox/flox. mrna encoding defective protein Transcription POMC Specific LepR KO.. POMC/Cre.

28 Leptin receptor deletion in POMC causes only modest obesity when compared to leptin receptor deletion in the entire CNS Body Weight (g) #,* * WT LepR/ POMC Cre LepR/ Nestin Cre do Carmo JM et al. Hypertension 57: , 2011

29 Leptin receptor deletion in POMC completely abolished leptin s ability to raise BP MAP (mmhg) Control # Leptin Infusion - 2 m g/kg/min * Recovery WT (n=6) LepR/POMC-Cre (n=7) 95 C2 C3 C4 C5 L1 L2 L3 L4 L5 L6 L7 R1 R2 R3 R4 R5 do Carmo JM et al. Hypertension 57: , 2011 Days

30 Mice with leptin receptor deletion in POMC neurons exhibit markedly attenuated BP and HR responses to acute air jet stress Air Jet Stress AUC (mmhg x 1 min) D Heart Rate 120 MAP 150 HR 80 # 100 # WT LepR flox/flox / POMC-Cre WT LepR flox/flox / POMC-Cre do Carmo JM et al. Hypertension 57: , 2011

31 Leptin receptors in POMC neurons are critical for leptin s ability to raise BP, but are not an important component of the appetite suppressing action of leptin. This suggests that CNS effects of leptin may be differentially regulated.

32 Leptin receptor signaling Jak2 Tyr Tyr P Irs2 Jak2 Tyr P P Irs2 PI3K PI3K Blood pressure regulation? Tyr985 Tyr985 P Shp2 Shp2 MAPK MAPK Thermogenesis, Glucose regulation? Tyr1138 Tyr1138 P STAT3 STAT3 Appetite

33 Does deletion of IRS2 signaling in POMC neurons attenuate or abolish the hypertensive effects of leptin?

34 Mice with IRS2 deletion in POMC neurons have similar body weight and food intake compared to control mice 50 Body Weight (g) 7 Food Intake (g) Weeks Weeks IRS2 flox/flox (n=6) IRS2-POMC (n=6) Unpublished observation (manuscript in preparation)

35 IRS2 deletion in POMC neurons did not abolish the effect of leptin to decrease food intake Food Intake (g) 6 Control Leptin Infusion-2mg/kg/min Recovery 5 4 Plasma Leptin = ng/ml 3 2 IRS2 flox/flox (n=9) 1 IRS2-POMC (n=9) C2 C3 C4 C5 L1 L2 L3 L4 L5 L6 L7 R 1 R2 R3 R4 R5 Unpublished observation (manuscript in preparation) Days

36 IRS2 deletion in POMC neurons did not attenuate the effect of leptin to reduce plasma glucose and insulin levels 200 Glucose (mg/dl) 45 Insulin (mu/ml) * * * * Control Leptin 0 Control Leptin IRS2 flox/flox (n=9) Unpublished observation (manuscript in preparation) IRS2-POMC (n=9) * p<0.05 compared to control period

37 D MAP (mmhg) IRS2 deletion in POMC neurons abolished the chronic blood pressure effects of leptin 8 C Leptin Infusion-2mg/kg/min 6 IRS2 flox/flox (n=9) IRS2-POMC (n=9) Unpublished observation (manuscript in preparation) C L1 L2 L3 L4 L5 L6 L7 Days

38 The IRS2 signaling pathway in POMC neurons plays a major role in mediating the effects of leptin on BP, but not on appetite or glucose homeostasis.

39 D Heart Rate (beats/min) Leptin reverses the decrease in heart rate caused by uncontrolled diabetes 50 Diabetes Leptin or Vehicle Vehicle Leptin ICV Leptin IV R2 R4 Days da Silva AA et al. Am J Physiol - RICP, 2006

40 Heart Rate (beats/min) MC3/4-R antagonism prevented leptin s effect to raise heart rate back to control values in diabetic rats 450 Induction of Diabetes (Streptozotocin 50 mg/kg) MC3/4R Antagonist (SHU-9119, 1 nmol/hr, ICV) 400 Leptin (0.02 mg/kg/min, ICV) Days

41 D Heart Rate (beats/min) a 1 /b 1, 2 adrenergic blockade attenuated ~50% of leptin s effect to raise heart rate in diabetic rats 140 ICV Leptin Diabetes ICV Leptin + a 1 /b 1,2 Blockade ICV Leptin R1 R3 Days da Silva AA et al. Am J Physiol - RICP, 2006

42 Leptin increases sympathetic input to the heart of diabetic rats 120 Control Diabetic ICV Leptin D Heart Rate (bpm) ns P=0.06 P=0.06 Atropine Propranolol p= p=0.016 p<0.001 do Carmo J, Hall J, da Silva A. Am J Physiol - HCP, 2008

43 Intrinsic Heart Rate (bpm) Leptin increases intrinsic heart rate of diabetic rats back to prediabetic values p=0.019 p= ns Control Diabetic ICV Leptin do Carmo J, Hall J, da Silva A. Am J Physiol - HCP, 2008

44 Leptin restored baroreflex sensitivity in diabetic rats back to control values 100 DHR (bpm) Control Diabetic Leptin * 50 Bradycardia C D L * DMAP (mmhg) Tachycardia C D L * -50 * * * p<0.05 vs control -100 do Carmo J, Hall J, da Silva A. Am J Physiol - HCP, 2008

45 Chronic infusion of glucose was able to maintain hyperglycemia during ICV leptin treatment Blood Glucose (mg/100ml) Induction of Diabetes (STZ - 50 mg/kg) Leptin (0.02 mg/kg/min, ICV) Glucose (35% ml/hr, IV) do Carmo J, Hall J, da Silva A. Am J Physiol - HCP, 2008 Days

46 Infusion of glucose to maintain hyperglycemia did not prevent leptin s effect to raise heart rate in diabetic rats Heart Rate (beats/min) 450 Leptin (0.02 mg/kg/min, ICV) Glucose (35% ml/hr, IV) 400 Induction of Diabetes (Streptozotocin 50 mg/kg) do Carmo J, Hall J, da Silva A. Am J Physiol - HCP, 2008 Days

47 Take Home Messages Obesity is the leading cause of essential hypertension (caused by several mechanisms including sympathetic activation). The increased leptin levels in obesity appear to be a key link between obesity, sympathetic activation and hypertension. Activation of the brain melanocortin system is necessary for the development of obesity-hypertension and for leptin to exert its hypertensive effects.

48 Take Home Messages Activation of the IRS2 signaling pathway in POMC neurons is important for the BP effects of leptin but not for the appetite and metabolic actions of leptin. Understanding the CNS mechanisms by which the leptin-melanocortin system differentially regulates appetite, glucose homeostasis and cardiovascular function may reveal new targets for therapies with greater efficacy and less side-effects to treat obesity.

49 Acknowledgements University of Mississippi Medical Center Alex da Silva s Lab: J. Nathan Freeman Ahmad Adi John E. Hall s Lab: Jussara M. do Carmo, Ph.D. John Dubinion, Ph.D. Jay J. Kuo, Ph.D. Lakshmi S. Tallam, Ph.D. Eugene Shek, Ph.D. Megan Carlyle Vanderbilt Univ. School of Medicine Roger D. Cone, Ph.D. The Rockefeller University Jeffrey M. Friedman, M.D., Ph.D. Univ. of Texas Southwestern Joel K. Elmquist, DMV, Ph.D. Harvard Medical School Morris White, M.D., Ph.D. Supported by NIH PO1 HL51971 and AHA

50 Thank you!

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