Metabolic Regulation of Hsp60/Hsp10 Chaperone Complex Impacts on Hypothalamic Lipid Metabolism
Final Report Abstract
We are facing a steadily increase of diabetic patients worldwide. A key feature of diabetes is insulin resistance, a state where the metabolic hormone is unable to properly control glucose homeostasis, metabolism and food intake. Mitochondria are crucial organelles to provide cells and the entire organism with energy in form of ATP by using fuels such as glucose and fatty acids. Due to alterations in energy status, cells are equipped with adaptive responses, such as the mitochondrial unfolded protein response (UPRmt) or the integrated stress response (ISR) - here summarized as mitochondrial stress response (MSR) - to propagate mitochondrial homeostasis and metabolic health. The mitochondrial chaperone complex Hsp60/Hsp10 is an integral part of this response but dysregulated in the hypothalamus in diabetic conditions. We investigated causes and consequences of this dysregulation for hypothalamic function and overall metabolism with an emphasis on lipid metabolism. Our data revealed that this dysregulation is present in the hypothalamus of type 1 and type 2 diabetic mouse models, suggesting that proper insulin action is a crucial modulator of this response. Indeed, we were able to demonstrate that insulin regulates the MSR in neurons and the hypothalamus. By regulating this response, especially the mitochondrial chaperone Hsp60, insulin enhanced mitochondrial function and regulated autophagy. Importantly, preventive intranasal insulin treatment of mice decreased high fat diet food intake and weight gain with increased expression of MSR genes in the hypothalamus, suggesting a beneficial effect of a proper regulated MSR on metabolism. To further assess the global effect of a dysregulated MSR on obesity development, a phenotype observed in diabetic conditions, we used a heterozygous Hsp60 knockout mouse model which exhibited a 50% reduction of Hsp60 protein levels. Unexpectedly, Hsp60+/- mice were protected against diet-induced obesity and exhibited decreased insulin resistance and increased energy expenditure compared to control mice. Interestingly, the reduction of Hsp60 had a major impact on adipose tissue development causing a reduction of mass, hyperplasia, increased mitochondrial protein synthesis and autophagy, indicators of an increased adipose tissue turnover. Yet as already published, these mice will suffer from neurodegeneration while aging. To understand the impact of a dysregulated Hsp60/Hsp10 complex on neuronal homeostasis and metabolism in detail, we decreased Hsp60´s co-chaperone Hsp10 in the hypothalamus using a lentiviral approach. This scientific approach unveiled the function of hypothalamic Hsp10 on mitochondrial homeostasis, insulin action and hypothalamic lipid metabolism. The reduction of Hsp10 in hypothalamic neurons caused mitochondrial dysfunction with increased mitochondrial fission and oxidative stress. Moreover, these neurons were insulin resistant and exhibited altered fatty acid metabolism with decreased expression of mitochondrial acyl-CoA dehydrogenases, key enzymes facilitating fatty acid oxidation. In line, the saturated fatty acids palmitate and stearate were elevated in Hsp10 knockdown (KD) cells. Subsequently we were able to show that the presence of elevated palmitate levels was instrumental for insulin and IGF-1 resistance in the hypothalamus and defined insulin receptor as a novel suppressor of palmitate-induced neuroinflammation. To further delineate the effect of reduced Hsp10 expression in the hypothalamus on metabolism, we generated mice with a mediobasal hypothalamic-specific reduction of Hsp10. These mice showed unaltered food intake, energy expenditure and body weight development, but exhibited altered liver metabolism with transient hepatic insulin resistance, signs of liver inflammation and increased expression of markers of hepatic gluconeogenesis. These data indicate that Hsp10 in the hypothalamus is a novel regulator of the brainliver axis. Lastly, we tested whether a dysregulated MSR altered sphingolipid metabolism in the hypothalamus, as human and mice with mutations of Hsp60 suffer from neurodegeneration with decreased myelin content. Indeed, a reduction of Hsp10 in hypothalamic neurons reduced sphingomyelin content, suggesting that the dysregulation of hypothalamic MSR impacted not only metabolism but also brain health. Overall, we identified the metabolic regulation of the Hsp60/Hsp10 complex in the hypothalamus, defined its effect on metabolism and obesity development and highlighted the importance of this complex on hypothalamic function and lipid metabolism.
Publications
- Deciphering brain insulin receptor and IGF1 receptor signaling. J Neuroendocrinol. 2016 Nov;28(11)
Kleinridders A
(See online at https://doi.org/10.1111/jne.12433) - Domain-dependent effects of insulin and IGF-1 receptors on signaling and gene expression Deciphering brain insulin receptor and IGF1 receptor signaling. Nat Commun. 2017 Mar 27;8:14892
Cai W, Sakaguchi M, Kleinridders A, Gonzalez-Del Pino G, Dreyfuss JM, O'Neill BT, Ramirez AK, Pan H, Winnay JN, Boucher J, Eck MJ, Kahn CR
(See online at https://doi.org/10.1038/ncomms14892) - Crosstalk of Mitochondria With Brain Insulin and Leptin Signaling. Front Endocrinol (Lausanne). 2018 Dec 14;9:761
Kleinridders A, Ferris HA, Tovar S.
(See online at https://doi.org/10.3389/fendo.2018.00761) - Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest. 2018 Jun 4. pii: 99366
Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, Li ME, Yu R, Kleinridders A, Pothos EN, Kahn CR
(See online at https://doi.org/10.1172/JCI99366) - Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism? Front Endocrinol (Lausanne). 2018 Apr 26;9:196
Castro JP, Wardelmann K, Grune T, Kleinridders A
(See online at https://doi.org/10.3389/fendo.2018.00196) - Regional differences in brain glucose metabolism determined by imaging mass spectrometry. Mol Metab. 2018 Jun;12:113-121
Kleinridders A, Ferris HA, Reyzer ML, Rath M, Soto M, Manier ML, Spraggins J, Yang Z, Stanton RC, Caprioli RM, Kahn CR
(See online at https://doi.org/10.1016/j.molmet.2018.03.013) - Impact of Brain Insulin Signaling on Dopamine Function, Food Intake, Reward, and Emotional Behavior. Curr Nutr Rep. 2019 Apr 18
Kleinridders A, Pothos EN
(See online at https://doi.org/10.1007/s13668-019-0276-z) - Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain. Mol Metab. 2019 Mar;21:68-81
Wardelmann K, Blümel S, Rath M, Alfine E, Chudoba C, Schell M, Cai W, Hauffe R, Warnke K, Flore T, Ritter K, Weiß J, Kahn CR, Kleinridders A
(See online at https://doi.org/10.1016/j.molmet.2019.01.001) - Insulin: Schützender Anpassungsmechanismus im Gehirn. Diabetologie und Stoffwechsel 14 (03), 178-179
A Kleinridders
(See online at https://doi.org/10.1055/a-0902-2123) - Molecular effects of dietary fatty acids on brain insulin action and mitochondrial function. Biol Chem. 2019 Feb 28.
Chudoba C, Wardelmann K, Kleinridders A.
(See online at https://doi.org/10.1515/hsz-2018-0477) - Appetite Control. (2020) In: Offermanns S., Rosenthal W. (eds) Encyclopedia of Molecular Pharmacology. Springer, Cham
Kleinridders A., Joost H.G.
(See online at https://doi.org/10.1007/978-3-030-21573-6_21-1) - GPx3 dysregulation impacts adipose tissue insulin receptor expression and sensitivity, J Clin Invest. Insight
Robert Hauffe, Vanessa Stein, Chantal Chudoba, Tanina Flore, Michaela Rath, Katrin Ritter, Mareike Schell, Kristina Wardelmann, Stefanie Deubel, Johannes F Kopp, Maria Schwarz, Kai Kappert, Matthias Blüher, Tanja Schwerdtle, Anna P Kipp, Andre Kleinridders
(See online at https://doi.org/10.1172/jci.insight.136283)
