Increased density of inhibitory noradrenergic parenchymal nerve fibers in hypertrophic islets of Langerhans of obese mice.
OBJECTIVE
We sought to identify mechanisms of beta cell failure in genetically obese mice. Little is known about the role of pancreatic innervation in the progression of beta cell failure. In this work we studied adrenergic innervation, in view of its potent inhibitory effect on insulin secretion. We analyzed genetically obese ob/ob and db/db mice at different ages (6- and 15-week-old), corresponding to different compensatory stages in the course of beta cell dysfunction. 15 week-old HFD mice were also studied.


RESULTS
All mice were characterized by measures of plasma glucose, insulin, and HOMA. After perfusion, pancreata were dissected and studied by light microscopy, electron microscopy, and morphometry. Insulin, Tyrosine Hydroxylase-positive fibers and cells and Neuropeptide Y-positive cells were scored by immunohistochemistry. Islets of obese mice showed increased noradrenergic fiber innervation, with significant increases of synaptoid structures contacting beta cells compared to controls. Noradrenergic innervation of the endocrine area in obese db/db mice tended to increase with age, as diabetes progressed. In ob/ob mice, we also detected an age-dependent trend toward increased noradrenergic innervation that, unlike in db/db mice, was unrelated to glucose levels. We also observed a progressive increase in Neuropeptide Y-immunoreactive elements localized to the islet core.


CONCLUSIONS
Our data show increased numbers of sympathetic nerve fibers with a potential to convey inhibitory signals on insulin secretion in pancreatic islets of genetically obese animals, regardless of their diabetic state. The findings suggest an alternative interpretation of the pathogenesis of beta cell failure, as well as novel strategies to reverse abnormalities in insulin secretion.
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy.
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Giannulis
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy.
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Mondini
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy.
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Cinti
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy.
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Frontini
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy.
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Murano
Dpt of Medical, Surgical and Health Sciences, Clinical Medicine, University of Trieste, Trieste, Italy.
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Barazzoni
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy.
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Barbatelli
Naomi Berrie Diabetes Center, Dpt of Medicine, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA. Electronic address: da230@columbia.edu.
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Accili
Dpt of Experimental and Clinical Medicine, Obesity Center, University of Ancona (Politecnica delle Marche) and Azienda Ospedali Riuniti, 60020 Ancona, Italy. Electronic address: s.cinti@univpm.it.
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Cinti
D059331:Adrenergic Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D006984:Hypertrophy; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000294:innervation* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D009433:Neural Inhibition; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D009478:Neuropeptide Y; D014446:Tyrosine 3-Monooxygenase
Islets; Noradrenergic fibers; Obesity