MANF regulates hypothalamic control of food intake and body weight

Nat Commun. 2017 Sep 18;8(1):579. doi: 10.1038/s41467-017-00750-x.


The hypothalamus has a vital role in controlling food intake and energy homeostasis; its activity is modulated by neuropeptides and endocrine factors. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor that is also localized in the endoplasmic reticulum (ER) in neurons. Here we show that MANF is highly enriched in distinct nuclei of the mouse hypothalamus, and that MANF expression in the hypothalamus is upregulated in response to fasting. Increasing or decreasing hypothalamic MANF protein levels causes hyperphagia or hypophagia, respectively. Moreover, MANF triggers hypothalamic insulin resistance by enhancing the ER localization and activity of PIP4k2b, a kinase known to regulate insulin signaling. Our findings indicate that MANF influences food intake and body weight by modulating hypothalamic insulin signaling.MANF is a neurotrophic factor that is secreted but also mediates the unfolded protein response acting intracellularly. Here, the authors show that MANF expression in the brain is influenced by nutritional cues, and hypothalamic MANF influences food intake and systemic energy homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Body Weight / genetics
  • Body Weight / physiology*
  • Eating / genetics
  • Eating / physiology*
  • Endoplasmic Reticulum Stress / genetics
  • Female
  • Gene Expression
  • Hypothalamus / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • PC12 Cells
  • RNA Interference
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction


  • MANF protein, mouse
  • Nerve Growth Factors