Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain

Kristina Wardelmann, Sabine Blümel, Michaela Rath, Eugenia Alfine, Chantal Chudoba, Mareike Schell, Weikang Cai, Robert Hauffe, Kathrin Warnke, Tanina Flore, Katrin Ritter, Jürgen Weiß, C. Ronald Kahn, André Kleinridders

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Objective: Insulin action in the brain controls metabolism and brain function, which is linked to proper mitochondrial function. Conversely, brain insulin resistance associates with mitochondrial stress and metabolic and neurodegenerative diseases. In the present study, we aimed to decipher the impact of hypothalamic insulin action on mitochondrial stress responses, function and metabolism. Methods: To investigate the crosstalk of insulin action and mitochondrial stress responses (MSR), namely the mitochondrial unfolded protein response (UPRmt) and integrated stress response (ISR), qPCR, western blotting, and mitochondrial activity assays were performed. These methods were used to analyze the hypothalamic cell line CLU183 treated with insulin in the presence or absence of the insulin receptor as well as in mice fed a high fat diet (HFD) for three days and STZ-treated mice without or with insulin therapy. Intranasal insulin treatment was used to investigate the effect of acute brain insulin action on metabolism and mitochondrial stress responses. Results: Acute HFD feeding reduces hypothalamic mitochondrial stress responsive gene expression of Atf4, Chop, Hsp60, Hsp10, ClpP, and Lonp1 in C57BL/6N mice. We show that insulin via ERK activation increases the expression of MSR genes in vitro as well as in the hypothalamus of streptozotocin-treated mice. This regulation propagates mitochondrial function by controlling mitochondrial proteostasis and prevents excessive autophagy under serum deprivation. Finally, short-term intranasal insulin treatment activates MSR gene expression in the hypothalamus of HFD-fed C57BL/6N mice and reduces food intake and body weight development. Conclusions: We define hypothalamic insulin action as a novel master regulator of MSR, ensuring proper mitochondrial function by controlling mitochondrial proteostasis and regulating metabolism.

Original languageEnglish
Pages (from-to)68-81
Number of pages14
JournalMolecular Metabolism
Volume21
DOIs
StatePublished - Mar 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

  • Autophagy
  • Brain insulin signaling
  • Intranasal insulin
  • Mitochondrial function
  • Mitochondrial stress response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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