Leptin regulation of Hsp60 impacts hypothalamic insulin signaling

Kleinridders, André; Lauritzen, Hans P.M.M.; Ussar, Siegfried; Christensen, Jane H.; Mori, Marcelo A.; Bross, Peter; Kahn, C. Ronald

doi:10.1172/jci67615

Cited by 112 publications

(116 citation statements)

References 72 publications

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“…This mitochondrial chaperonin is a ubiquitous molecule with multiple roles in health and disease [62,63] recently found to be involved in insulin resistance [62]. HSP60 appears to be modulated by leptin in the hypothalamus of obese and diabetic mice and decreased levels of leptin were found in accordance with the reduced presence of HSP60 [64]. Decreased levels of leptin, as mentioned above, were found correlated with the reduced presence of Hsp60.…”

Section: Discussionmentioning

confidence: 67%

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

Nuzzo

Picone

Baldassano³

et al. 2015

CAR

105

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Alzheimer's disease (AD) is an aging-related multi-factorial disorder to which metabolic factors contribute at what has canonically been considered a centrally mediated process. Although the exact underlying mechanisms are still unknown, obesity is recognized as a risk factor for AD and the condition of insulin resistance seems to be the link between the two pathologies. Using mice with high fat diet (HFD) obesity we dissected the molecular mechanisms shared by the two disorders. Brains of HFD fed mice showed elevated levels of APP and Aβ 40 /Aβ 42 together with BACE, GSK3β and Tau proteins involved in APP processing and Aβ accumulation. Immunofluorescence, Thioflavin T staining experiments, confirmed increased Aβ generation, deposition in insoluble fraction and plaques formation in both the hippocampus and the cerebral cortex of HFD mice. Presence of Aβ 40 and Aβ 42 in the insoluble fraction was also shown by ELISA assay. Brain insulin resistance was demonstrated by reduced presence of insulin receptor (IRs) and defects in Akt-Foxo3a insulin signaling. We found reduced levels of phospho-Akt and increased levels of Foxo3a in the nuclei of neurons where proapototic genes were activated. Dysregulation of different genes related to insulin resistance, especially those involved in inflammation and adipocytokines synthesis were analyzed by Profiler PCR array. Further, HFD induced oxidative stress, mitochondrial dysfunction and dynamics as demonstrated by expression of biomarkers involved in these processes. Here, we provide evidence that obesity and AD markers besides insulin resistance are associated with inflammation, adipokine dyshomeostasis, oxidative stress and mitochondrial dysfunction, all mechanisms leading to neurodegeneration.

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Section: Discussionmentioning

confidence: 67%

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

Nuzzo

Picone

Baldassano³

et al. 2015

CAR

105

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“…It has been shown that insulin resistance in the brain (36), like insulin resistance in skeletal muscle (34), is associated with mitochondrial dysfunction, and mitochondrial dysfunction has been associated with neurological disorders (41). Examination of isolated mitochondria from brains of control and NIRKO mice using a Seahorse XF24 Extracellular Flux Analyzer revealed a 28 ± 9% reduction in basal oxygen consumption rate (OCR) compared with control (P < 0.05), even by 4 mo of age.…”

Section: Resultsmentioning

confidence: 99%

“…Insulin resistance and type 2 diabetes are well documented to be associated with mitochondrial dysfunction in classical metabolic tissues, such as muscle (34) and liver (35), and we have recently demonstrated that obesity-induced insulin resistance is also associated with altered mitochondrial function in the hypothalamus (36). Patients with major depression have also been shown to exhibit mitochondrial dysfunction in the brain (37).…”

mentioning

confidence: 87%

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders

Kleinridders

Cai

Cappellucci³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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363

249

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Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders. A s life expectancy in humans has increased, we are faced with a worldwide epidemic of age-related diseases such as type 2 diabetes (T2D) and Alzheimer's disease (1). These parallel epidemics may not be coincidental. Indeed, studies have demonstrated an association between diabetes and a variety of brain alterations including depression, age-related cognitive decline, Alzheimer's disease, and Parkinson's disease (2, 3). In addition, individuals with both type 1 and type 2 diabetes have been shown to have a variety of abnormalities in brain imaging, including altered brain activity and connectivity by functional MRI (4, 5), altered microstructure by diffusion tensor imaging (6, 7), and altered neuronal circuitry in the striatum (8). Conversely, patients with Alzheimer's disease show signs of central insulin resistance with increased insulin receptor substrate (IRS) 1 serine phosphorylation in the brain and decreased insulin concentrations in the cerebrospinal fluid (9, 10). Furthermore, pilot clinical trials of intranasal insulin administered to individuals with Alzheimer's disease suggest decreased rates of cognitive decline (11).These observations in humans have been mechanistically supported by studies in rodents and cultured cells, which have shown that insulin receptor signaling in brain has an important role in central regulation of metabolism and may also be crucial for proper brain function (12)(13)(14). We have previously demonstrated that mice with insulin resistance in brain due to targeted deletion of the insulin receptor (NIRKO mice) develop hyperphagia, mild obesity, reduced fertility, and decreased counterregulatory response to hypoglycemia (15, 16). NIRKO mice also display glycogen synthase kinase 3 beta (GSK3-beta) activation, resulting in hyperphosphorylation of tau protein, a hallmark of e...

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“…There are other aspects of mitochondrial biology that are linked to insulin resistance, such as mitochondrial quality control (151,152), fission/fusion (153) and proteostasis (154), and reviewed in (155)) that are also regulated by ROS production (reviewed in (156)). …”

mentioning

confidence: 99%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

125

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Insulin resistance is a major risk factor for numerous diseases including Type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of 'common' insulin resistance. Despite considerable effort, the mechanisms that contribute to 'common' insulin resistance are not resolved. There is universal agreement that extracellular perturbations such as nutrient excess, hyperinsulinemia, glucocorticoids or inflammation trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway, but rather is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states such as fasting, and that in the presence of chronic nutrient excess this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a pathophysiological state where cells display reduced responsiveness to the glucose-lowering activity of insulin. While there are rare cases where mutations in genes associated with insulin signaling or lipodystrophy cause insulin resistance, for the most part insulin resistance is associated with obesity and thus a state of positive energy balance. This form of insulin resistance is frequently associated with hyperinsulinemia, increased waist circumference or visceral adiposity, metabolic dyslipidemia with high triglycerides and low HDL, and hepatic steatosis, features collectively referred to as the metabolic syndrome. We refer to this as "common insulin resistance". Here, both insulin-dependent glucose disposal and suppression of glucose output are impaired, albeit the relative degree of impairment in each process can vary between individuals (1-3).In this review we focus on the literature surrounding insulin resistance in muscle and adipose tissue, and specifically on insulin-stimulated glucose transport into myocytes and adipocytes within these tissues. Impaired insulin action in other tissues, most notably the liver (4, 5), brain (6, 7) and vasculature (8), also play a key role in whole body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in 'proximal' insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt. We argue that common insulin resistance arises ...

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Leptin regulation of Hsp60 impacts hypothalamic insulin signaling

Cited by 112 publications

References 72 publications

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

Insulin resistance in brain alters dopamine turnover and causes behavioral disorders

Muscle and adipose tissue insulin resistance: malady without mechanism?

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