CONSEQUENCES OF ELEVATED SYSTEMIC NEUROPEPTIDE Y AND NORADRENALINE LEVELS TO PERIPHERAL MICROVESSEL VASOCONSTRICTION AND BRAIN STEM ASTROCYTES

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 685-694-Mechanisms of Obesity
Basic
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-690
Carlo Casale*1, Shen Lei2, Nephtali Marina1, Rosaire Gray3, Pratik Sufi3 and Vidya Mohamed-Ali1
1Adipokines and Metabolism Research Group, Centre for Clinical Pharmacology & Division of Medicine, University College London, 2University College London, 3NLOSS, Whittington Hospital, London
Background:  Approximately ~20% of a Caucasian cohort, despite morbid obesity, remains metabolically healthy (MHO), retaining insulin sensitivity and lower risk of associated pathologies.

Aim:  To determine if elevated peripheral neuropeptide Y (NPY) and noradrenaline (NA), previously studied as markers of heightened SNS activity, 1) mediate the heterogeneity of obesity pathology and are modified by weight loss, 2) adversely activate astrocytes of the brain stem, responsible for physiological control of blood pressure, heart rate and baroreflex sensitivity through neuronal interaction.

Methods:  Consenting, Caucasian, subjects were studied prior to and following surgical weight loss.  The MHO cohort had no T2DM or CVD and fasting insulin <6.5 miU/ml, the remaining were classified as Metabolic Syndrome (MeS) or diabetic (DM).  Adipokines, NPY and NA were determined by ELISA, morphology by histology, insulin resistance by HOMA-IR and vasocontractility of adipose arterioles by wire myography. Primary human brain stem astrocytes were exposed to varying NA and NPY levels in vitro and cytokine release and gene expression changes determined.

Results: Despite matched BMI, MeS had higher fasting insulin (p<0.001), HOMA-IR (p<0.001), triglycerides (p<0.001), glucose (p=0.007) and lower adiponectin (p = 0.016) than MHO cohort and accompanied by adipocyte hypertrophy (p<0.001). Circulating NPY was lowest in MHO {DM 16.1(8.15-27), MeS 11.2(4.9-14.8) and MHO [8.6 (3.5-12) pg/ml}.  Similar trends were apparent in adipose tissue NPY and NA protein. NPY mediated a less powerful, transient vaso-contractility in MHO arterioles compared to those from the MeS patients. In the presence of NA the NPY mediated vaso-contractility was of a higher magnitude and sustained. Brain stem astrocytes showed an increase in inflammatory cytokine secretion (IL-6 and MCP-1) on exposure to both NA and NPY, but no change when exposed to either on their own. Expression of adrenergic receptors B2 and A2 also appears to change at the mRNA level with NPY exposure.

Successful weight loss led to improved insulin sensitivity only in MeS and DM subjects (p=0.03).  Circulating adiponectin increased and free fatty acids decreased significantly in all groups.  The change in NPY levels did not reach significance in any group.

Conclusion:  Concerted elevation in circulating NPY and tissue NA are associated with deteriorating metabolic status, impaired vaso-constriction of resistance vessels and inflammation in brain stem astrocytes. The pathologies mediated by elevated NPY and NA appear less reversible by weight loss.

Nothing to Disclose: CC, SL, NM, RG, PS, VM

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm