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Abstract
Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
Highlights
Altered energy homeostasis, insulin resistance, and mitochondrial abnormalities are features of type 2 diabetes (T2D)
The co-chaperone heat shock protein 10 (Hsp10) forms a lid structure, modulates Hsp60 activity, and controls the ATPase cycle during the event of refolding proteins [5,6]. This chaperone complex folds more than 250 proteins, including the antioxidative enzyme superoxide dismutase 2 (SOD2), and has been shown to interact with more than 300 proteins [7,8,9]. This chaperone complex belongs to the mitochondrial stress response (MSR), a mitochondrial-nuclear signaling pathway, which helps mitochondria to cope with stress and reinstate proper mitochondrial function [10]
Since mitochondrial dysfunction and altered lipid metabolism are linked to inflammation and insulin resistance, we investigated whether a reduction of Hsp10 affected these responses
Summary
Insulin resistance, and mitochondrial abnormalities are features of type 2 diabetes (T2D). The co-chaperone Hsp forms a lid structure, modulates Hsp activity, and controls the ATPase cycle during the event of refolding proteins [5,6] This chaperone complex folds more than 250 proteins, including the antioxidative enzyme superoxide dismutase 2 (SOD2), and has been shown to interact with more than 300 proteins [7,8,9]. This chaperone complex belongs to the mitochondrial stress response (MSR), a mitochondrial-nuclear signaling pathway, which helps mitochondria to cope with stress and reinstate proper mitochondrial function [10]. Mutations of Hsp even cause spastic paraplegia 13 and a fatal demyelinating leukodystrophy [12,13], showing the immense impact of mitochondrial protein folding on brain function
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