Local regulation of fat metabolism in peripheral nerves.
We comprehensively analyzed gene expression during peripheral nerve development by performing microarray analyses of premyelinating, myelinating, and postmyelinating mouse sciatic nerves, and we generated a database of candidate genes to be tested in mapped peripheral neuropathies. Unexpectedly, we identified a large cluster of genes that are (1) maximally expressed only in the mature nerve, after myelination is complete, and (2) tied to the metabolism of storage (energy) lipids. Many of these late-onset genes are expressed by adipocytes, which we find constitute the bulk of the epineurial compartment of the adult nerve. However, several such genes, including SREBP-1, SREBP-2, and Lpin1, are also expressed in the endoneurium. We find that Lpin1 null mutations lead to lipoatrophy of the epineurium, and to the dysregulation of a battery of genes required for the regulation of storage lipid metabolism in both the endoneurium and peri/epineurium. Together with the observation that these mutations also result in peripheral neuropathy, our findings demonstrate a crucial role for local storage lipid metabolism in mature peripheral nerve function, and have important implications for the understanding and treatment of peripheral neuropathies that are commonly associated with metabolic diseases such as lipodystrophy and diabetes.
Verheijen
Mark H G
MH
Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, USA.
Chrast
Roman
R
Burrola
Patrick
P
Lemke
Greg
G
D017667:Adipocytes / Q000502:physiology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D050356:Lipid Metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D005810:Multigene Family; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D010711:Phosphatidate Phosphatase; D012584:Sciatic Nerve / Q000196:embryology / Q000378:metabolism* / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase