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

Proper control of mitochondrial function in the brain is of utter importance for normal brain function and physiology. Mitochondrial dysfunction has been observed in neurodegenerative and metabolic disorders, such as type 2 diabetes. Normally, mitochondria adapt to altered nutrient supply via the mitochondrial stress response. Wardelmann, Blümel, Rath, and colleagues found that brain insulin signaling impacts mitochondrial stress responsiveness in the hypothalamus and thus affects mitochondrial function and metabolism. Their data offer new insight into how brain insulin regulates neuronal health, acts as a neuroprotective hormone, and regulates metabolism.

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.