Metabolic stress drives sympathetic neuropathy within the liver

Cell Metab. 2021 Mar 2;33(3):666-675.e4. doi: 10.1016/j.cmet.2021.01.012. Epub 2021 Feb 4.


The nervous system instructs the body's metabolism, including that in the liver. However, the neural anatomy of the liver under either normal or metabolically stressed conditions remains to be unequivocally assessed. Here, we examined neural distributions in the mouse, nonhuman primate, and human livers with advanced 3D imaging. We observed that neural innervations within the liver are predominantly sympathetic, but not parasympathetic, inputs. Moreover, we discovered the profound and reversible loss of such sympathetic innervations during metabolic challenges. This hepatic sympathetic neuropathy was caused by TNFα derived from CD11b+ F4/80+ immune cells under high-fat-diet (HFD) condition. We further demonstrated that the Sarm1 deletion mitigated the hepatic sympathetic neuropathy and improved metabolic parameters in HFD-challenged mice. Mechanistically, the sympathetic neurotransmitter norepinephrine attenuated the immune-cell inflammation that would otherwise trigger the insulin insensitivity of hepatocytes. These results together reveal the previously unrecognized neuropathic event in the liver with metabolic relevance.

Keywords: 3D neural anatomy; Sarm1; high-fat diet; inflammation; liver; sympathetic neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Diet, High-Fat
  • Humans
  • Liver / anatomy & histology
  • Liver / metabolism*
  • Lymphocytes / cytology
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Norepinephrine / pharmacology
  • Stress, Physiological*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Armadillo Domain Proteins
  • Cytoskeletal Proteins
  • SARM1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Norepinephrine