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Prolonged high fat diet ingestion, obesity, and type 2 diabetes symptoms correlate with phenotypic plasticity in myenteric neurons and nerve damage in the mouse duodenum

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Abstract

Symptoms of diabetic gastrointestinal dysmotility indicate neuropathy of the enteric nervous system. Long-standing diabetic enteric neuropathy has not been fully characterized, however. We used prolonged high fat diet ingestion (20 weeks) in a mouse model to mimic human obese and type 2 diabetic conditions, and analyzed changes seen in neurons of the duodenal myenteric plexus. Ganglionic and neuronal size, number of neurons per ganglionic area, density indices of neuronal phenotypes (immunoreactive nerve cell bodies and varicosities per ganglion or tissue area) and nerve injury were measured. Findings were compared with results previously seen in mice fed the same diet for 8 weeks. Compared to mice fed standard chow, those on a prolonged high fat diet had smaller ganglionic and cell soma areas. Myenteric VIP- and ChAT-immunoreactive density indices were also reduced. Myenteric nerve fibers were markedly swollen and cytoskeletal protein networks were disrupted. The number of nNOS nerve cell bodies per ganglia was increased, contrary to the reduction previously seen after 8 weeks, but the density index of nNOS varicosities was reduced. Mice fed high fat and standard chow diets experienced an age-related reduction in total neurons, with bias towards neurons of sensory phenotype. Meanwhile, ageing was associated with an increase in excitatory neuronal markers. Collectively, these results support a notion that nerve damage underlies diabetic symptoms of dysmotility, and reveals adaptive ENS responses to the prolonged ingestion of a high fat diet. This highlights a need to mechanistically study long-term diet-induced nerve damage and age-related impacts on the ENS.

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Acknowledgments

This study was funded by the University of Idaho, IBEST and Idaho INBRE (NIH Grant Nos. P20 RR016454 and P20 GM103408). Work done by M. Gericke was supported by Deutsche Forschungsgemeinschaft grant number DFG-SFB 1052/1: ‘Obesity mechanisms’ (projects A04). The authors would like to acknowledge Joe T. Schmaltz, Rachel Siemens, Sky Hembree and Spencer Dean for their assistance with staining and quantification procedures.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Idaho, 875 Perimeter Drive 3051, LSS 252, Moscow, ID, 83844-3051, USA

    Chloe M. Stenkamp-Strahm, Yvonne E. A. Nyavor, Adam J. Kappmeyer, Sarah Horton & Onesmo B. Balemba

  2. Institute for Anatomy, University of Leipzig, Liebigstraße 13, 04103, Leipzig, Germany

    Martin Gericke

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  1. Chloe M. Stenkamp-Strahm
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  2. Yvonne E. A. Nyavor
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  6. Onesmo B. Balemba
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Correspondence to Onesmo B. Balemba.

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Stenkamp-Strahm, C.M., Nyavor, Y.E.A., Kappmeyer, A.J. et al. Prolonged high fat diet ingestion, obesity, and type 2 diabetes symptoms correlate with phenotypic plasticity in myenteric neurons and nerve damage in the mouse duodenum. Cell Tissue Res 361, 411–426 (2015). https://doi.org/10.1007/s00441-015-2132-9

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  • DOI: https://doi.org/10.1007/s00441-015-2132-9

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