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. Author manuscript; available in PMC: 2015 Oct 9.
Published in final edited form as: Curr Opin Investig Drugs. 2009 Oct;10(10):1049–1060.

Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis

Suzanne M de la Monte 1,2,3,, Lisa Longato 1, Ming Tong 1,4, Jack R Wands 1,4
PMCID: PMC4600072  NIHMSID: NIHMS724183  PMID: 19777393

Abstract

Recent studies have linked obesity, type 2 diabetes mellitus (T2DM) or non-alcoholic steatohepatitis (NASH) to insulin resistance in the brain, cognitive impairment and neurodegeneration. Insulin resistance compromises cell survival, metabolism and neuronal plasticity, and increases oxidative stress, cytokine activation and apoptosis. T2DM/NASH has been demonstrated to be associated with increased ceramide generation, suggesting a mechanistic link between peripheral insulin resistance and neurodegeneration because ceramides mediate insulin resistance and can cross the blood-brain barrier (BBB). Peripheral insulin resistance diseases may potentially cause brain insulin resistance via a liver-brain axis of neurodegeneration as a result of the trafficking of ceramides across the BBB. Therapy that includes insulin-sensitizing agents may help prevent brain insulin resistance-mediated cognitive impairment.

Keywords: BBB, blood-brain barrier, ceramide, dementia, insulin resistance, liver-brain axis, obesity, type 2 diabetes mellitus

Introduction

Although aging is the strongest risk factor for Alzheimer’s disease (AD), data also suggest that type 2 diabetes mellitus (T2DM) and dyslipidemic conditions either contribute to, or serve as cofactors in, the pathogenesis of AD [1]. This hypothesis is supported by epidemiological data that suggest an increased risk of developing mild cognitive impairment (MCI), dementia or AD in individuals with T2DM [27]. Mechanistically, an increased risk of dementia could be linked to chronic hyperglycemia, insulin resistance, oxidative stress, the accumulation of advanced glycation end products, the increased production of proinflammatory cytokines and microvascular disease [2]. However, because most of these markers represent core characteristics of T2DM and non-alcoholic steatohepatitis (NASH) [811], both of which are peripheral insulin resistance diseases, it is likely that toxic/injurious agents produced in the body and associated with obesity mediate similar effects in different target organs; injurious agents or toxins that cause insulin resistance in adipose tissue and skeletal muscle could result in T2DM, whereas the same insult in the liver could cause NASH/metabolic syndrome and, in the brain, could cause MCI or early AD-type neurodegeneration. The link between peripheral insulin resistance and brain insulin resistance with concomitant cognitive impairment may potentially be mediated by a liver-brain axis of neurodegeneration, which is caused by the excessive trafficking of neurotoxic lipids, including ceramides, across the blood-brain barrier (BBB); this review summarizes experimental and epidemiological data supporting this hypothesis.

Insulin resistance and cognitive impairment

Peripheral insulin resistance diseases

T2DM, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and NASH are insulin resistance diseases that have increasing rates of prevalence worldwide. T2DM is characterized by hyperglycemia, hyperinsulinemia and insulin resistance, and is frequently associated with obesity [1214]. Metabolic syndrome develops in the context of visceral obesity, and is associated with T2DM, dyslipidemia and hypertension [13]. NAFLD represents a spectrum ranging from simple hepatic steatosis to NASH, and is not associated with infection or excessive alcohol consumption [12]. NAFLD is characterized by hepatocellular lipid accumulation (mainly in the form of triglycerides), resulting in greater than 5 to 10% increases in liver weight [15]. Up to 24% of the general population, and 50 to 70% of obese individuals have NAFLD [12,16]. Although hepatic steatosis (ie, fatty liver in which at least 5 to 10% of the liver weight is due to fat, mainly triglyceride, accumulation) is generally benign and reversible, approximately one-third of patients with NAFLD eventually progress to NASH (ie, hepatic steatosis accompanied by significant inflammation, hepatocellular injury, cell death and fibrosis), which is more serious because this disease can lead to end-stage liver disease, cirrhosis or hepatocellular carcinoma. Factors controlling the progression of NAFLD to NASH are not completely understood, but roles for lipotoxicity, oxidative stress and proinflammatory mediators in the development of this disease have been suggested [17,18].

The relationship between peripheral insulin resistance and cognitive impairment

The rates of prevalence of AD, obesity, T2DM, NAFLD, NASH and metabolic syndrome have all increased in the past several decades [1925]. The probable interrelatedness among these syndromes and disorders is suggested by several observations: (i) the increased risk of developing MCI, dementia or AD in individuals with T2DM [7,26] or obesity/dyslipidemic disorders [27]; (ii) the correlations between severity of brain insulin resistance and neuropathological stages of AD [2831]; (iii) the development of cognitive impairment and neurodegeneration in experimental T2DM with or without obesity [32,33]; (iv) the presence of AD-type neurodegeneration and cognitive impairment following the intracerebral administration of streptozotocin (a prodiabetic drug) in animals [3438]; (v) improvements in cognitive performance observed following treatment with insulin-sensitizing agents or intranasal insulin in animal models [39] or patients with AD or MCI [4045]; and (vi) the similar molecular, cellular and biochemical mechanisms controlling fundamental abnormalities in T2DM, NASH and AD [7,4651].

Conversely, the systematic analysis of postmortem brains from individuals with T2DM [5255] or experimental animal models of diet-induced obesity with T2DM and NASH [56,57] demonstrated generally mild neurodegenerative lesions, despite evidence of cognitive impairment. In humans, the major adverse effects of T2DM on brain structure include cerebral vascular disease, increased infarcts and ischemic lesions, and greater β-amyloid peptide burdens [55]. However, a further analysis of the insulin signaling pathway is needed to determine whether T2DM/NASH-associated cognitive impairment is mediated by insulin resistance and reduced cholinergic function, as demonstrated in animal models [56,57]. Given that obesity, MCI, AD, T2DM, NASH and metabolic syndrome are all associated with insulin resistance (ie, the impaired ability to respond to insulin), these diseases may share common etiologies. In addition, the lack of complete epidemiological overlap among these diseases suggests that specific organ systems may be differentially affected by exposure to similar conditions, including high dietary fat intake, resulting in dissimilar degrees of insulin resistance with disparate long-term outcomes.

Insulin, insulin-like growth factors and brain functions

In brain as well as in other organs and tissues, insulin transmits progrowth and prosurvival signals by activating intracellular pathways, beginning with ligand binding to cell surface receptors; insulin receptor substrate type 1 (IRS-1) is the major substrate of both the insulin receptor (IR) and the IGF-1 receptor. The subsequent activation of receptor tyrosine kinases increases tyrosine phosphorylation of IRS-1 and IRS-2, the signaling of which promotes cell growth, survival and energy metabolism in the CNS [58]. A critical feature of insulin/ IRS signal transduction is the interaction of tyrosyl-phosphorylated IRS-1/IRS-2 with adaptor molecules that contain Src homology domains (eg, Grb2 and the p85 subunit of PI3K) to promote mitogenesis, cell survival, gene expression, energy metabolism and motility [5860]. Although an almost identical signaling pathway exists for insulin-like growth factor type 1 (IGF-1), at physiological concentrations, insulin and IGF-1 selectively bind to their own distinct receptors (the IR and IGF-1 receptor, respectively) to mediate somewhat distinct functions.

In the CNS, insulin/IGF-1 signaling cascades are almost identical to signaling cascades in the liver (although IRS-2 instead of IRS-1 is the major docking protein in the brain) [58]. Insulin, IGF-1 and IGF-2, and their corresponding receptors, are abundantly expressed in neurons [58,61,62] and oligodendroglia [6365] throughout the brain. Regionally, the highest expression levels are in the hypothalamus, temporal lobe and cerebellum [58]. Both insulin and IGF-1 support neuronal growth, survival, differentiation and metabolic functions, and promote neurite outgrowth, migration, protein synthesis, neuronal cytoskeletal protein expression and nascent synapse formation [6670]. As a result, these trophic factors stimulate neuronal plasticity and neurotransmitter functions [58,7174], both of which are required for learning and memory. In addition, IGF-1 has a dominant role in regulating oligodendrocyte survival and myelination [66], while insulin modulates food intake, glucose homeostasis, growth and metabolic activity [58,75]. Thus, sustained impairments in insulin and IGF-1 signaling could cause cellular degeneration, oxidative stress, DNA damage, proinflammatory cytokine activation and apoptosis, with accompanying negative effects on cognition and behavior.

Peripheral versus brain insulin resistance

Insulin resistance is characterized by the reduced ability of cells to respond to insulin, and is associated with impaired glucose utilization and lipid metabolism, resulting in increased oxidative stress and inflammation [76]. Reduced responsiveness to insulin can be mediated by impaired receptor binding, the downregulation or loss of receptors, or the reduced activation of downstream signaling through receptors and IRS molecules [7680]. In peripheral insulin resistance diseases, the main tissues affected include skeletal muscle, adipose tissue and the liver. In the brain, insulin resistance caused by or associated with chronic alcohol exposure, obesity with T2DM, experimental depletion of IRs, exposure to nitrosylating agents or AD is similarly manifested by impaired binding to IRs, reduced glucose utilization, reduced energy metabolism, increased oxidative stress and neuroinflammation [39,56,57,78,8185], as well as the impaired expression and function of insulin-responsive genes required for cognitive-motor functions and plasticity [56,78,8183]. Therefore, the CNS can be a target of insulin resistance that is mediated by either brain-specific diseases such as AD, or peripheral insulin resistance diseases.

Hepatic steatosis, toxic lipids and insulin resistance

Steatohepatitis and insulin resistance

Although associations are recognized between peripheral insulin resistance and cognitive impairment, and between brain insulin resistance and neurodegeneration, the underlying mechanisms for these associations are not readily apparent. Observations on potential mechanisms of brain insulin resistance in obesity or T2DM were derived from experiments demonstrating that insulin resistance mediated by hepatic steatosis or steatohepatitis was associated with the increased generation of ceramides [56,86]. To verify that hepatic insulin resistance was a consequence of hepatic steatosis, IR and IGF receptor binding, gene expression and signaling were measured in livers from several animal models, including models of diet-induced obesity with NASH [56], chronic high-fat diet feeding without obesity [82], chronic alcohol feeding [79], models in which hepatic steatosis or steatohepatitis was a prominent feature, and of nitrosamine-mediated injury [86]. Without exception, steatohepatitis was associated with reduced IR binding, IR gene expression, IR tyrosine phosphorylation, IR tyrosine kinase activation, signaling through IRS-1 and insulin-responsive gene expression, and with increased oxidative stress and adduct (ie, DNA, protein and lipid) accumulation. Moreover, treatment with insulin-sensitizing agents reduced hepatic insulin resistance in patients with NASH [87,88] and in rats chronically administered alcohol [89]. Therefore, irrespective of cause, hepatic steatosis and steatohepatitis appear to have pivotal roles in the pathogenesis of hepatic insulin resistance.

Steatohepatitis and toxic lipid generation

Insulin stimulates lipogenesis, which results in increased triglyceride storage in the liver [90,91]. While this process is generally benign and well tolerated, disturbances in homeostasis caused by endoplasmic reticulum stress, oxidative damage, mitochondrial dysfunction, inflammation and/or altered membrane lipid composition can shift the balance toward a state of insulin resistance [90,92]. Insulin resistance promotes lipolysis [93], which generates toxic lipids, including ceramides, that further impair insulin signaling, mitochondrial function and cell viability [92,94,95].

Lipotoxicity and ceramides

Lipotoxicity is a state of cellular dysfunction caused by intracellular lipid overload, which activates stress signaling and proinflammatory cytokines, increases the production of reactive oxygen species and toxic lipid intermediates, and inhibits mitochondrial β-oxidation [14,96,97]. Although fatty acids are widely recognized as mediators of lipotoxicity [98,99], roles for sphingolipids and ceramides have also been suggested more recently [100106]. Ceramides comprise a family of lipid signaling molecules generated from fatty acids and sphingosine [100,107,108]. Long-chain ceramides of 16 to 24 carbons in length are naturally occurring and distributed in cell membranes, and have both structural and functional roles. These molecules influence signaling pathways that regulate cell growth, proliferation, motility, adhesion and differentiation [94,100,109,110]. In contrast, ceramides with shorter carbon chains (two to six carbons) promote cell senescence, cytotoxicity, apoptosis, insulin resistance and inflammation, and inhibit survival and growth [94,100,109,110].

Lipids stored in hepatocytes are mobilized by lipolysis and the degradation of sphingomyelin; ceramides are generated during the biosynthesis or degradation of triglycerides and sphingomyelin [94,104,106,111,112]. Ceramides can be generated biochemically by several approaches: (i) de novo synthesis through ceramide synthase- and serine palmitoyltransferase-mediated condensation of serine and palmitic acids [113116]; (ii) the hydrolysis of sphingomyelin through the activation of neutral or acidic sphingomyelinases [108,116]; or (iii) the degradation of complex sphingolipids and glycosphingolipids localized in late endosomes and lysosomes [107]. The inhibition of ceramide synthesis and accumulation prevents obesity-mediated insulin resistance [104,117]. Ceramides adversely alter cellular functions and cause apoptosis by modulating the phosphorylation states of proteins, including proteins that regulate insulin signaling [118]. In addition, ceramides mediate their anti-cell survival effects by activating enzymes such as IL-1β-converting enzyme-like proteases, which promote apoptosis [107], and by inhibiting Akt phosphorylation and kinase activity [119] via the stimulation of protein phosphatase 2a [120].

Disease-associated lipolysis, a feature of insulin resistance, is initiated by critical levels of stress in the endoplasmic reticulum and mitochondrial dysfunction [97,121123]. In such states, ceramides cause insulin resistance by activating proinflammatory cytokines and inhibiting insulin-stimulated signaling through PI3K-Akt [124127]. In obesity, adipose tissue, skeletal muscle and the liver exhibit abnormalities in sphingolipid metabolism that result in increased ceramide production, inflammation and the activation of proinflammatory cytokines, and in impairments in glucose homeostasis and insulin responsiveness [100,112,116,128]. In patients with NASH [129] and in C57BL/6 mice with diet-induced obesity, T2DM and NASH [116], ceramide levels in adipose tissue are elevated; the mechanism likely involves increased activation of sphingomyelin transferase and acidic and neutral sphingomyelinases [107]. In both genetic and diet-induced obesity models, ceramide accumulation in skeletal muscle and adipose tissue may also mediate insulin resistance [102,116,129].

Ceramides and related toxic lipids as mediators of insulin resistance

Ceramides and related molecules are hypothesized to be critical mediators of insulin resistance diseases such as neurodegeneration because these molecules can be generated in liver, visceral adipose or brain tissues [100,114,116,130]; can cause insulin resistance [100]; are cytotoxic [100]; have been demonstrated to be increased in the CNS in various dementias, including AD [130133]; and are lipid soluble [110] and therefore likely able to cross the BBB. In diet-induced obesity, mechanisms of enhanced ceramide production in adipocytes and accompanying insulin resistance have been well documented [100,104,106,134136]. In contrast, there is limited evidence of the role of ceramides in relation to hepatic insulin resistance, and no large-scale epidemiological studies have been conducted that significant demonstrate correlative relationships between NASH or NAFLD and cognitive impairment. To address this paucity of information, studies were conducted to determine if ceramide exposure could cause hepatic insulin resistance, if other models of steatohepatitis led to increased pro-ceramide gene expression in the liver, and if hepatic steatosis and steatohepatitis resulted in increased ceramide levels (immunoreactivity) in the liver and serum. In vitro treatment with synthetic C(2) or C(6) ceramide significantly impaired hepatocellular viability, mitochondrial function and insulin-responsive gene expression. In addition, C(2) and C(6) ceramides, but not C(2)D (inactive) ceramide or vehicle, inhibited insulin-stimulated signaling downstream of the IR and IRS-1. Therefore, the results suggest that ceramides are hepatotoxic and can cause hepatic insulin resistance [Longato L, Tong M, Wands JR, de la Monte SM: unpublished data].

Ceramides are enzymatically generated through the actions of several enzymes (Figure 1) [110]. To assess the potential role of ceramides in the pathogenesis of insulin resistance in the context of hepatic steatosis or steatohepatitis, hepatic pro-ceramide mRNA levels were measured by quantitative (q)RT-PCR in mouse or rat models of steatohepatitis, including diet-induced obesity, NASH, and low-dose nitrosamine (N-nitrosodiethylamine) exposure [56,137] [Tong M, Longato L, de la Monte SM: unpublished data]. Irrespective of etiology, the mean levels of several pro-ceramide mRNA transcripts were significantly increased in livers from models of steatohepatitis caused by chronic high fat feeding, low-dose nitrosamine exposure or both. In addition, ELISA and dot blot analyses revealed significantly elevated levels of ceramide immunoreactivity in the livers and sera of mice with diet-induced obesity or rats that developed NASH following low-dose nitrosamine exposures [56,116,137], and in patients with NASH [Promrat K, Longato L, de la Monte S, Wands JR: unpublished data]. These studies demonstrated that pro-ceramide gene expression and hepatic and serum ceramide levels increase in steatohepatitis from several causes, and that ceramide exposure is hepatotoxic and causes hepatocellular insulin resistance.

Figure 1. Ceramide synthesis and metabolism pathways.

Figure 1

Ceramides are generated de novo by the condensation of palmitate-CoA and serine in reactions catalyzed by serine palmitoyltransferases. Ceramides are also formed through the hydrolysis of sphingomyelin by sphingomyelinases, or through the acylation of sphingosine by ceramide synthases. Ceramides can undergo phosphorylation by ceramide kinase. Several steps in these pathways are reversible through the activation of enzymes.

Toxic lipids and neurodegeneration

Ceramides: Neurotoxicity and neuronal insulin resistance

Given that toxic lipids (including ceramides) can cross the BBB, and can cause insulin resistance by interfering with important phosphorylation events [107,119,120] and by activating proinflammatory cytokines [100,138,139], studies to assess the role of liver-derived ceramides as mediators of neurodegeneration were conducted. In vitro studies demonstrated that exposure to synthetic C(2) and/or C(6) ceramide caused neuronal insulin resistance with reduced viability, mitochondrial function and cholinergic function, and increased oxidative stress, DNA damage, lipid peroxidation and amyloid precursor protein (APP) expression [140]. Correspondingly, dopaminergic neuronal cells treated with a C(2) ceramide analog exhibited reduced activation of the PI3K-Akt pathway and IGF-1-stimulated energy metabolism [119]. Moreover, preliminary in vivo intraperitoneal ceramide treatment caused brain insulin resistance, neurodegeneration and motor deficits, mimicking the effects of chronic alcohol exposure [Tong M, de la Monte SM: unpublished data]. Therefore, these studies indicated that ceramides generated or delivered from sources outside of the CNS could cause CNS neuronal insulin resistance, neurodegeneration and neurocognitive deficits.

Endogenous brain ceramides and neurodegeneration

CNS neurons and oligodendrocytes are responsive to and dependent on insulin, which promotes cell viability, energy metabolism, neurotransmitter synthesis, plasticity and myelin homeostasis in the brain [58,63,71]. Metabolic stresses impair oligodendrocyte functions such as myelin maintenance [64,72,74]. Because ceramides are generated in the brain during myelin turnover and degradation, factors that impair oligodendroglial function would be expected to increase local ceramide biosynthesis [133,141144]. Locally increased ceramide production has been demonstrated to increase brain insulin/IGF resistance, neuroinflammation and oxidative stress [100,106,112,125,136,145149]. Roles for ceramides as mediators of neuroinflammation, oxidative stress and neurodegeneration have been suggested or demonstrated in various diseases, including AD, motor neuron disease, multiple sclerosis and HIV dementia [133,150152]. However, in the context of T2DM or NASH, the degree to which neurotoxic ceramides contribute to neurodegeneration would likely correlate with the severity of steatohepatitis and lipid metabolic disequilibrium in the liver. Mechanistically, the increased generation of ceramides and other toxic lipids in the liver could mediate the adverse effects of these molecules on the structure and function of the CNS via a liver-brain axis of neurodegeneration. Consequential injury and degeneration of oligodendrocytes and white matter could exacerbate myelin degradation, and could result in increased local ceramide production, with concomitant activation of pro-oxidant and pro-death cascades.

Ceramides and the liver-brain axis of neurodegeneration

Given that NASH can be clinically associated with cognitive and neuropsychiatric dysfunction [153159], mechanisms of insulin signaling, pro-ceramide gene expression and ceramide levels in experimental models of NAFLD and NASH produced by chronic feeding with a high-fat diet and/or exposure to nitrosamine (submutagenic doses, ip) were investigated; all models demonstrated histopathological and biochemical evidence of neurodegeneration, as well as deficits in learning and memory [34,39,56,57,86]. Steatohepatitis associated with liver and brain insulin resistance was demonstrated by reductions in IR binding, IR gene expression, IR tyrosine kinase activation, insulin-responsive gene expression (including those genes required for energy metabolism or neurotransmitter synthesis) [34,39,56,57,86,137] [Tong M, Longato L, de la Monte SM: unpublished data], and increased oxidative stress. Using qRT-PCR analysis, steatohepatitis were demonstrated to be associated with the upregulated expression of multiple pro-ceramide genes in the liver in mouse [56] and rat models [137]. ELISA and dot blot analyses demonstrated higher mean levels of ceramide immunoreactivity in the liver and blood [137].

Thus, these results provide evidence that steatohepatitis causes hepatic insulin resistance, oxidative stress and injury to the CNS, with an increased production of cytotoxic ceramides that exacerbate hepatic insulin resistance, inflammation and CNS injury. Liver-derived cytotoxic lipids entering the circulation and capable of penetrating the BBB may represent primary mediators of CNS insulin resistance, oxidative stress and proinflammatory cytokine activation. In obesity or T2DM associated with NAFLD, NASH or metabolic syndrome, CNS injury and degeneration are possibly initiated by the peripheral (hepatic) production of toxic lipids, including ceramides, which cross the BBB and cause insulin resistance. With continued and sustained injury, particularly to oligodendrocytes and white matter, the degradation of myelin leads to increased endogenous ceramide production that exacerbates CNS insulin resistance, neuroinflammation, oxidative stress, metabolic impairment and neurotransmitter deficits, all of which contribute to deficits in neuronal plasticity. Cognitive impairment and brain insulin resistance arising in the contexts of obesity, T2DM, NASH or metabolic syndrome may be mediated via a liver-brain axis of neurodegeneration (Figure 2). In addition, proinflammatory cytokine-mediated injury, with the disruption of cell-to-cell junctions and the apoptosis of endothelial cells via the increased production of cytotoxic lipids, including ceramides, could result in increased BBB permeability [150,151,160]. This situation would allow further trafficking of toxic lipids to the brain from the periphery, thereby exacerbating the liver-brain axis of neurodegeneration. This hypothesis introduces a new approach to investigating disease mechanisms and strategies for developing non-invasive tools to monitor susceptibility to, and the progression of, neurodegeneration in the context of peripheral insulin resistance diseases.

Figure 2. The liver-brain axis of neurodegeneration in type 2 diabetes mellitus.

Figure 2

Neuronal survival, neurotransmitter function and plasticity require intact insulin and insulin-like growth factor (IGF) signaling in the brain. Direct insults stemming from environmental exposures and aging threaten the integrity of the expression of insulin and IGF, and the function of insulin receptor (IR)- and IGF-1 receptor (IGF-1R)-bearing cells. In type 2 diabetes mellitus (T2DM), obesity and non-alcoholic steatohepatitis (NASH), peripheral insulin resistance leads to increased oxidative stress and the generation of toxic ceramides, particularly in the liver. Ceramides cross the blood-brain barrier and cause CNS insulin/IGF resistance, oxidative stress, inflammation and neurodegeneration. Therefore, peripheral insulin resistance diseases may precipitate, propagate or exacerbate Alzheimer’s disease via a liver-brain axis of neurodegeneration.

PPAR agonists as a potential therapeutic strategy for insulin resistance-mediated neurodegeneration

Obesity-mediated insulin resistance in the liver and brain shares many features in common with T2DM, suggesting that insulin-sensitizing drugs such as PPAR agonists, which are used to treat T2DM, may have therapeutic relevance for liver and brain insulin resistance-mediated diseases. PPARs (α,δ and γ) are expressed in the liver [89] and brain [39], and have important roles in regulating lipid metabolism, inflammation, glucose utilization and insulin-responsive gene expression [161,162]. PPAR agonists function at the level of the nucleus to activate insulin-responsive genes and signaling mechanisms.

PPAR rescue of brain insulin resistance-mediated neurodegeneration

PPARα, PPARδ and PPARγ have been demonstrated to be expressed in adult human brains, with PPARδ being the most abundant of the three isoforms [163]. Treatment with PPAR agonists was shown to prevent brain atrophy, and to preserve IR- and IGF receptor-bearing CNS neurons, cholinergic homeostasis and myelin gene expression; these compounds, particularly PPARδ agonists, also prevented insulin resistance-induced deficits in learning and memory [39]. In addition, critical CNS indices of oxidative stress, including microglial and astrocyte activation, increased p53, nitric oxide synthase and NADPH oxidase gene expression, lipid peroxidation, DNA damage, APP expression, and tau phosphorylation [164167], were decreased by treatment with PPAR agonists [34,39,163].

Studies investigating the treatment of insulin resistance in humans with MCI or early AD have produced somewhat promising results. Most notable are those studies in which individuals diagnosed with early AD exhibited improvements or stabilization of their cognitive impairment following treatment with intranasal insulin or a PPARγ agonist [42,44,168171]. However, one caveat is that these studies were relatively short in duration and had a small number of participants. While these approaches are warranted hypothetically, the mechanistic and feasibility challenges involved require addressing several needs: (i) to develop sensitive and predictive biomarkers assays of early AD versus MCI for patient selection; (ii) to better characterize the benefits of different PPAR agonist subclasses, given the relatively high levels of PPARδ expression in the CNS and previously demonstrated effectiveness of specific agonists in rescuing AD-type neurodegeneration [146]; and (iii) to develop an assay panel to objectively monitor CNS insulin resistance for correlations with assessments of cognitive function. Finally, given the overall magnitude of the public health problem of cognitive impairment, potential long-term preventive options for supporting the integrity of insulin/IGF signaling mechanisms in both the periphery and CNS should be considered. In this regard, preliminary studies in animal models have demonstrated that the use of soy protein isolate and its bioactive constituents (ie, genistein, daidzein and β-conglycinin), which function as antioxidants and insulin-sensitizing agents [172174], could prevent or reduce hepatic and brain insulin resistance [Tong M, Ziplow J, Conoway A, de la Monte SM: unpublished data].

Conclusion

The growing epidemic of insulin resistance diseases, including T2DM and NASH, is coupled with increasing rates of cognitive impairment and AD. Although available data do not support the hypothesis that obesity, T2DM or NASH cause AD, these diseases can contribute to the pathogenesis and/or rate of progression of AD. Mechanistically, T2DM and NASH represent disordered metabolic states that are associated with the increased production of toxic lipids, including ceramides, that can cause insulin resistance, inflammation, oxidative stress and cell death. Studies using various experimental models have demonstrated that steatohepatitis, irrespective of etiology, increases hepatic (and probably visceral) ceramide production, and that chronic steatohepatitis with insulin resistance is associated with cognitive impairment and neurodegeneration. Given that ceramides can cross the BBB, steatohepatitis with peripheral insulin resistance might potentially establish a liver-brain axis of neuroinflammation and neurodegeneration. Monitoring peripheral blood ceramide levels may help to identify individuals with T2DM or NASH who are at risk for developing cognitive impairment. In addition, treatment with insulin-sensitizing agents, or possibly the implementation of dietary measures that promote insulin sensitivity, may help to reduce the incidence of cognitive impairment or the progression of MCI to AD.

Acknowledgments

The authors are supported by grants AA-02666, AA-02169, AA-11431, AA-12908 and AA-16126 from the NIH.

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