Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus

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.

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

“…In addition, the increased expression of heat shock protein 70 in the brain can improve insulin sensitivity and glycemic control [121]. Decreased mitochondrial chaperones heat shock protein 60 and 10 in the hypothalamus of T2DM lead to mitochondrial dysfunction and trigger neuronal insulin resistance, suggesting that defects in mitochondrial protein quality control may play an important role in the development of insulin resistance [122,123]. However, the link between mitochondrial protein quality control system and cognitive impairment in T2DM remains largely unknown.…”

Fibrillar Alpha-Synuclein Alters the Intracellular Chaperone Levels within Hours of Its Internalization

“…The weakening of HSP10 may represent another significant factor contributing to the decline in mitochondrial function during the progression of PD. Studies have demonstrated a correlation between the knockdown of this chaperone and the occurrence of hypometabolism and oxidative stress . This suggests that under chronic exposure to F-αSyns, the essential energy required for the survival of substantia nigra dopaminergic neurons, lacking myelin and having high energy demands, may not be adequately supplied.…”

“…Studies have demonstrated a correlation between the knockdown of this chaperone and the occurrence of hypometabolism and oxidative stress. 36 This suggests that under chronic exposure to F-αSyns, the essential energy required for the survival of substantia nigra dopaminergic neurons, lacking myelin and having high energy demands, may not be adequately supplied. Consequently, this could lead to a detrimental effect on these neurons compared with the impact of the PD process alone.…”

Toward the Decipherment of Molecular Interactions in the Diabetic Brain

“…Reduction in co-chaperone Hsp10, which modulates Hsp60 activity, was also sufficient to cause hypothalamic insulin resistance with acute liver insulin resistance, decreases in subunit protein levels of the ETC complexes, and mitochondrial dysfunction in T2DM mice. Interestingly, Hsp10 knockdown in murine hypothalamic cells increased saturated fatty acids (FA) and decreased monounsaturated FA content [ 116 ]. The shift from unsaturated FAs to saturated FAs in cardiolipin, the inner mitochondrial membrane phospholipid essential for the proper function of the respiratory enzymes and the assembly of the ETC into supercomplexes, was also observed in the brain cortex of streptozotocin-rats [ 93 ].…”