Just where fat is deposited in the body and to what degree a person may benefit from a lifestyle intervention depends, among other things, on how sensitive the brain is to insulin.
If the person’s brain responds sensitively to the hormone, a significant amount of weight can be lost, unhealthy visceral fat reduced, and the weight loss can be maintained over the long term.
However, If the person’s brain responds only slightly or not at all to insulin, the person only loses some weight at the beginning of the intervention and then experiences weight regain.
Over the long term, the visceral fat also increases. These are the results of a long-term study by the German Center for Diabetes Research (DZD), Helmholtz Zentrum München and Tübingen University Hospital which has now been published in Nature Communications.
To which extent body fat has an unhealthy effect depends primarily on where it is stored. If fat accumulates in the abdomen, this is particularly unfavorable. This is because the visceral fat releases numerous neurotransmitters that affect blood pressure, influence the secretion of the hormone insulin and can cause inflammation.
This increases the risk of diabetes, cardiovascular disease and certain types of cancer.
The subcutaneous fat which accumulates on the buttocks, thighs and hips has no adverse health effects. However, it is still unclear why fat storage does not occur in the same place in all people. Studies in the Tübingen Lifestyle Intervention Program (TULIP) [1] suggest that brain insulin responsiveness could play an important role here.
They showed that people with a high insulin sensitivity in the brain benefit significantly more from a lifestyle intervention with a diet rich in fiber and exercise than people with insulin resistance in the brain.
Not only did they lose more weight, they also had a healthier fat distribution. But how does insulin sensitivity affect the distribution of body fat and weight in the long term?
Researchers from the German Center for Diabetes Research (DZD), Helmholtz Zentrum München and Tübingen University Hospital investigated this question in a long-term study.
For this purpose, they recorded the follow-up data of 15 participants over a period of nine years, in which the insulin sensitivity in the brain was determined by magnetoencephalography before the start of a 24-month lifestyle intervention.
High insulin sensitivity associated with reduction in visceral fat and weight
It was found that insulin action in the brain not only determines body weight, but also the distribution of fat in the body. “Subjects with high insulin sensitivity in the brain benefited from the lifestyle intervention with a pronounced reduction in weight and visceral fat.
Even after the lifestyle intervention had ended, they only regained a small amount of fat during the nine-year follow-up,” said the head of the study, Professor Martin Heni from Tübingen University Hospital.
In contrast, people with brain insulin resistance only showed a slight weight loss in the first nine months of the program. “Afterwards, their body weight and visceral fat increased again during the following months of lifestyle intervention,” said first author PD Dr. Stephanie Kullmann from the IDM.
Since the insulin action in the hypothalamus is crucial for the regulation of peripheral energy metabolism, the researchers also investigated how insulin sensitivity in this area of the brain is related to the distribution of body fat.
For this purpose, they examined a cross-sectional cohort of 112 participants. The analysis of the data showed that people with high insulin sensitivity in the hypothalamus form little visceral fat. However, insulin sensitivity has no influence on the mass of subcutaneous fat.
Our study reveals a novel key mechanism that regulates fat distribution in humans. Insulin sensitivity in the brain determines where fat is deposited, “said Heni, summarizing the results.
Since visceral fat not only plays a role in the development of type 2 diabetes, but also increases the risk of cardiovascular disease and cancer, the study results may also open up new approaches for treatment options beyond metabolic diseases.
The researchers in Tübingen are already working on new therapies to abolish insulin resistance in the brain and thus have a beneficial effect on body fat distribution.
Effects of Brain Insulin Resistance on Hippocampus- Dependent Functions
Data reviewed in the previous paragraphs support the view that changes of either insulin signaling or insulin sensitivity in the hippocampus may alter molecular pathways involved in synaptic plasticity and adult neurogenesis, thereby leading to reduced “mindspan” (the maintenance of mental abilities throughout life) and increased risk of neurodegeneration (Kodl and Seaquist, 2008).
Accordingly, while calorie restriction furthers neuronal survival and improves cognitive function (Fusco and Pani, 2013), the excess of nutrients harms the brain health and accelerates cognitive decline (Elias et al., 2012; Sellbom and Gunstad, 2012).
Nutrient excess causes hyper-activation of insulin signaling in all tissues expressing IR, leading to the desensitization of IR-dependent molecular cascades.
BIR decreases the ability of brain cells to respond to insulin and abolishes both metabolic and cognitive effects of this hormone (Kullmann et al., 2016). Specifically, this deficiency could be caused by lower expression of IR or poor activation of insulin signaling.
IR downstream effectors may become insensitive to the insulin stimulation, resulting in inability of brain cells to respond to the hormone and leading to impairment of brain plasticity. In the Western world, the incidence of metabolic disorders, including insulin resistance, obesity and T2D, is increasing at alarming rates in parallel with the prevalence of cognitive decline (Cukierman-Yaffee, 2009).
Obesity and inflammation affect the insulin transport to the brain (Ketterer et al., 2011) and low expression of IR has been reported in patients with T2D (Kullmann et al., 2016).
However, patients with T2DM and/or obesity showed decreased insulin levels in the cerebrospinal fluid despite higher levels of this hormone in their plasma (Heni et al., 2014). In the following paragraphs, we will summarize the mechanisms underlying the detrimental effects of BIR on hippocampal plasticity and cognition, and the epidemiological and experimental evidence supporting a link between BIR and AD.
Alterations of Hippocampal Plasticity in BIR Models
High-fat diet (HFD) is a well-established animal model of metabolic disorders (Wong et al., 2016). HFD induces obesity by compromising β-cell functions, promoting hyper-glycaemia, whole-body insulin resistance, and dyslipidemia, and increasing free fatty acids in the blood. Many studies have investigated the structural and functional changes of neuroplasticity in experimental models of insulin resistance (Fadel and Reagan, 2016).
More specifically, HFD produces detrimental effects on brain functions including decreased neurogenesis in the dentate gyrus (Lindqvist et al., 2006), alteration of BBB integrity (Freeman and Granholm, 2012) and changes in both spine density and synapse formation (Stranahan et al., 2008a).
HFD also impairs insulin signaling in the hippocampus and reduces the expression of synaptic proteins PSD-95 and synaptopodin (Arnold et al., 2014). However, the most significant effects occur on activity-dependent synaptic plasticity. Indeed, Zucker rats show impairment in LTP at CA3–CA1 synapses in parallel with loss of insulin sensitivity (Kamal et al., 2013).
Moreover, IR heterozygous knockout mice display normal levels of both basal synaptic transmission and LTP that, however, fails to be consolidated due to reduced Akt activation (Nisticò et al., 2012).
Obesity and T2D have been demonstrated to induce hippocampal insulin resistance through different metabolic changes including alteration of hypothalamic-pituitary-adrenal (HPA) axis leading to elevated levels of glucocorticoids (Plotsky et al., 1992). Accordingly, glucocorticoids stimulation inhibits translocation of GLUT4 to the plasma membrane in the rat hippocampus (Piroli et al., 2007).
Moreover, Stranahan et al. showed that restoring physiological levels of glucocorticoids in insulin resistant db/db mice rescued the impairment of hippocampal synaptic plasticity (Stranahan et al., 2008b).
A different model of BIR is obtained by intracerebral injection of streptozotocin, which impairs cognitive function by reducing the activity of the neuroprotective protein SIRT1 (Du et al., 2014). As mentioned before, SIRT1 cooperates with the transcription factor CREB promoting the CREB-dependent expression of the neuroplasticity-related gene Bdnf (Jeong et al., 2012).
To better clarify the functional role of hippocampal insulin resistance, Grillo et al. (2015) silenced the expression of IR in the hippocampus by injecting lentiviral particles harboring IR antisense sequence.
This experimental model showed deficits in hippocampal synaptic transmission and spatial learning, in parallel with downregulation of NMDA subunit GluN2B expression and lower phosphorylation of AMPA subunit GluA1, without altering peripheral metabolic parameters (i.e., body weight, adiposity, and glucose homeostasis) (Grillo et al., 2015).
Recently, we described a novel link between BIR and altered glutamate receptor function underlying the HFD-dependent impairment of hippocampal synaptic plasticity (Spinelli et al., 2017).
In particular, we found that HFD induced accumulation of palmitic acid and increased FOXO3a-dependent expression of palmitoyl-transferase zDHHC3 leading to GluA1 hyper-palmitoylation in the hippocampus.
Accordingly, in vitro stimulation of hippocampal neurons with a cocktail of insulin and palmitic acid replicated the in vivo molecular changes, inhibiting the GluA1 localization at the synaptic membrane and AMPA currents at glutamatergic synapses. Finally, either silencing of zDHHC3 or overexpression of the palmitoylation-deficient GluA1 mutant in the hippocampus abolished the insulin resistance-dependent impairment of synaptic plasticity (Spinelli et al., 2017).
Of course, aberrant palmitoylation of other zDHHC3 targets (e.g., GABAA RƔ2) may contribute to the detrimental effects of HFD on hippocampus-dependent learning and memory. However, our study adds a new layer to the hippocampal synaptic plasticity regulation by insulin signaling deterioration and proposes a novel molecular mechanism potentially linking BIR and cognitive decline.
Other mechanisms underlying fatty acid-driven learning deficits involve cholesterol dysmetabolism, oxidative stress, endothelial dysfunctions, and neurotrophin depletion. Mice fed with HFD show higher levels of reactive oxygen species (ROS), superoxide, and peroxynitrite into the brain, leading to lower level of brain-derived neurotrophic factor (BDNF) and impaired cognition performance evaluated by spatial task (Wu et al., 2004).
Moreover, epidemiological studies showed that diets enriched in cholesterol (HCD) were associated with poor cognitive performance in humans (Requejo et al., 2003). HCD diet also induced impairment of spatial and working memory due to microglial activation and alteration of the BBB integrity in rats (Chen et al., 2018).
Interestingly, feeding obese rodents with HFD inhibited the transport through the BBB of neuroendocrine molecules, such as ghrelin and leptin, which promote synaptic plasticity and cognitive functions (Banks et al., 2008; Kanoski et al., 2013; Mainardi et al., 2017).
Finally, HFD has been shown to induce activation of microglia and astrocytes, and increase of pro-inflammatory cytokines/mediators such as cyclooxygenase 2, TNF-α, IL-1-β, and IL-6 in the hippocampus of mice (Thirumangalakudi et al., 2008; Duffy et al., 2019).
In summary, metabolic diseases affecting insulin signaling may impair the synaptic function through a plethora of molecular mechanisms targeting neurons, astrocytes, endothelial or inflammatory cells.
Cognitive Impairment in BIR Models
Epidemiological evidence indicate that metabolic alterations occurring in T2D, such as hyper-glycaemia and hyper-insulinaemia, positively correlate with cognitive impairment and diabetic patients exhibit higher susceptibility to develop dementia (Cukierman-Yaffee, 2009).
Dysregulation of glucose homeostasis increases the risk of dementia in both diabetic and non-diabetic patients (Crane et al., 2013) and is associated with reduced hippocampal volume and cognitive decline (Kerti et al., 2013).
Furthermore, longitudinal studies demonstrated that also Type 1 diabetes (T1D) patients were affected by mild-severe cognitive impairment related to the age of onset of the disease and the microvascular complications (Moheet et al., 2015; Nunley et al., 2015).
Insulin administration is crucial to promote glucose homeostasis in these patients and to reduce the vascular complications but it increases the risk for hypoglycemic episodes, which negatively impact on cognitive functions (Desrocher and Rovet, 2004). However, the role of hypo- or hyper-insulinemia in T1D-related cognitive alterations has still to be clarified.
Numerous clinical studies revealed worse cognitive performance and earlier age incidence of all-cause dementia in subjects with T2D (Davis et al., 2017; Callisaya et al., 2019). Accordingly, meta-analysis studies showed that in diabetic patients the risk for all types of dementia is increased by 60–73% (Gudala et al., 2013; Chatterjee et al., 2016).
However, alteration of brain insulin signaling may negatively impact on brain function also in the absence of T2D and before the onset of obesity. Several studies have demonstrated deficits in hippocampal-dependent learning and spatial memory associated with Western diet intake (Molteni et al., 2002; Kanoski and Davidson, 2010).
Interestingly, when Kanoski and Davidson (2010) investigated both hippocampus-dependent and hippocampus-independent memory retention ability after different Western diet treatments, they found that only spatial memory impairments occurred after short-term consumption.
This suggests that hippocampus is a brain area very sensitive to metabolic stress, and memory impairment may arise before the development of diet-induced metabolic alterations in peripheral tissues. Accordingly, few days of HFD regimen were sufficient to cause cognitive impairment in rats evaluated with MWM test (Murray et al., 2009). High caloric intake also affected hippocampus-dependent non-spatial learning and mem
ory tasks and these results were related to changes of the BBB integrity. Specifically, high energy diet consumption reduced the expression of tight junction proteins selectively causing increased blood-to-brain permeability in the hippocampus (Kanoski and Davidson, 2010).
The observed learning and memory deficits are strikingly similar to the poor task performance and cognitive impairment observed in patients with mild or severe metabolic derangements, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of diet-dependent cognitive alterations.
Therefore, cognitive dysfunction related to HFD or obesity in otherwise healthy individuals may be due to decreased insulin signaling and development of BIR in the hippocampus (McNay et al., 2010).
Nevertheless, peripheral insulin resistance and diet-induced obesity are correlated with some other changes that may cause neurocognitive dysfunction. Indeed, they induce systemic and central inflammation with high levels of circulating pro-inflammatory interleukins that have been linked to impaired executive function (Trollor et al., 2012). Obesity also alters HPA axis causing enhanced secretion of glucocorticoids, which have been associated with reduced hippocampal volume, memory impairment and mood alterations (MacQueen and Frodl, 2011).
Moreover, mice specifically lacking the IR into the brain (NIRKO mice) display changes in dopamine turnover associated with anxiety and depressive-like behaviors (Kleinridders et al., 2015). In addition, diet-induced microbiota dysbiosis can impact on the gut-brain axis, thus promoting insulin resistance and cognitive impairment (Daulatzai, 2014). Finally, HFD exposure during early stages of life is associated with impaired learning and spatial memory (Boitard et al., 2012), suggesting that alteration of insulin signaling may negatively influence cognitive function at each stage of life.
Brain Insulin Resistance, Brain Aging and Neurodegenerative Diseases
While diabetes is known to increase the risk for dementia, the underlying mechanisms linking insulin resistance, T2D and AD are poorly understood. Undoubtedly, micro- and macro-vascular complications of T2D may increase the risk of cerebrovascular disease, cognitive impairment and vascular dementia (Gorelick et al., 2011). Moreover, white matter disease, alteration of the BBB and neuro-inflammation may play a pathophysiologic role (Hsu and Kanoski, 2014).
However, hyper-insulinaemia promotes the formation of advanced glucose end products and ROS causing neurotoxicity and brain damage (Brownlee, 2001). Despite insulin exerts a neurotrophic role at moderate concentrations, higher levels of the hormone may be associated with increased deposition of amyloid-β (Aβ) in the brain due to competition for their common and main clearance mechanism, the insulin-degrading enzyme (Farris et al., 2003).
In this regard, AD has been defined a form of type 3 diabetes, based on the evidence of BIR development in the AD brain (Steen et al., 2005; Bedse et al., 2015; Sposato et al., 2019). The insulin synthesis decreases during aging and AD progression in brain areas such as frontal cortex, hippocampus, and hypothalamus (Frolich et al., 1998). In addition,
Aβ inhibits insulin expression in astrocytes (Pitt et al., 2017). Together, these studies indicate a crosstalk between brain insulin signaling alteration and Aβ accumulation in neurodegenerative diseases. Accordingly, experimental data obtained from neuroimaging and biomarker studies revealed that T2D patients showed alterations of both brain glucose metabolism and cerebrospinal fluid including phosphorylated tau, which are reminiscent of changes observed in AD (Baker et al., 2011; Moran et al., 2015).
In addition, analysis of AD postmortem brains revealed insulin signaling alterations in hippocampal tissues resembling the biochemical features of insulin resistance in parallel with histopathological hallmarks of neurodegeneration (Talbot et al., 2012; Tramutola et al., 2015). Moreover, tau is hyper-phosphorylated in the brain of NIRKO mice (Schubert et al., 2004) and BIR has been associated with tau pathology in AD human brains (Yarchoan and Arnold, 2014).
Interestingly, T2D and AD also share several metabolic derangements promoting brain aging. AD patients show hyper-insulinaemia and decreased peripheral insulin sensitivity (Craft et al., 1996), whereas insulin levels in cerebrospinal fluid are reduced (Craft et al., 1998).
Accordingly, sustained peripheral hyper-insulinaemia can reduce the transport of insulin into the brain due to the lower expression of IR at the BBB (Schwartz et al., 1990). Brain insulin uptake is also impaired in both aging and AD independently by T2D (Frolich et al., 1998).
Recent evidence suggests that insulin may influence Aβ deposition and AD-dependent impairment of both synaptic plasticity and memory formation (Cholerton et al., 2013). Intranasal insulin administration has been demonstrated to improve cognitive function in humans (Hallschmid et al., 2007; Reger et al., 2008).
However, recent data about a clinical trial with mild cognitive impairment (MCI) or moderate AD patients revealed no significant effects of long-term intranasal insulin delivery on cognitive performance in memory task (Craft et al., 2017).
Finally, genetic and experimental data about insulin degrading enzyme and, more recently, the Aβ metabolism regulation by sortilin related VPS10 domain containing receptor 1 (SorCS1) gene suggest novel mechanistic links between BIR and AD (Lane et al., 2010; Wang et al., 2015). Thus, BIR seems to play a pivotal role at the crossroad between metabolic and neurodegenerative diseases, independently from the cerebrovascular mechanisms.
Biomarkers of Brain Insulin Resistance
In view of the close relationship among metabolic diseases, BIR and cognitive decline, it is emerging the need to identify biomarkers able to detect BIR before, or possibly even in the absence of, peripheral insulin resistance, that may be predictive of age- and dementia-related cognitive impairment. Ideal biomarkers should be reliable, simple to measure, non-invasive and inexpensive (Noel-Storr et al., 2013).
In this regard, the dosage of both Aβ and tau proteins in the cerebrospinal fluid is invasive and most likely indicative of a pathology already under development. For these reasons, in the last years several studies focused on evaluation of brain glucose metabolism and analysis of brain-derived extracellular vesicles extracted from the blood as biomarkers of BIR and early-phase cognitive decline.
Cerebral glucose metabolism is tightly correlated with neuronal activity (Simpson et al., 2007). Therefore, imaging of local brain hypo-metabolism can be used to visualize areas of reduced synaptic activity. The most frequently used method of brain metabolic imaging is positron emission tomography (PET) with (18F)fluorodeoxyglucose (FDG) (Cohen and Klunk, 2014).
Reduced cerebral glucose metabolism represents one of the earliest signs of AD, and studies in both humans and experimental models suggest that altered brain glucose metabolism is associated with AD progression (Kapogiannis and Mattson, 2011; Ishibashi et al., 2015).
Recent work have identified in GK rats reduced glutamine synthesis and impairment of the glutamate-glutamine cycle between astrocytes and neurons, driving to diabetes-induced neurodegeneration and cognitive dysfunction (Girault et al., 2017).
In a mouse model of AD, impaired glucose transport through the BBB and decreased cerebral lactate release during neuronal activity occur at early stages of the phenotype (Merlini et al., 2011). Dysregulated brain glucose metabolism resembling changes observed in AD patients has been observed in metabolic disorders such as obesity or T2D (Tschritter et al., 2006, 2007).
However, whether neuroimaging changes of brain glucose metabolism anticipate the onset of neurodegeneration or are related to the development of BIR in the same brain areas remain still poorly understood.
More recently, molecular strategies have been developed to selectively isolate brain-derived exosomes (BDE) from biological fluids (Tschritter et al., 2006, 2007; Fiandaca et al., 2015; Goetzl et al., 2016). Exosomes are extracellular vesicles carrying information (e.g., proteins, lipids, and nucleic acids) to distant cells, which are emerging as novel potential biomarkers for human diseases (Tkach and Thery, 2016).
Several pathogenic proteins that are involved in neurodegenerative diseases, including AD, are loaded into vesicles and then extracellularly secreted via exosomes (Rajendran et al., 2006; Sharples et al., 2008). More importantly, changes of insulin resistance molecular markers (i.e., higher serine phosphorylation and lower tyrosine phosphorylation of IRS-1) have been found in neural-derived exosomes extracted from blood of AD patients compared to age- and gender-matched patients with frontotemporal dementia or T2D (Kapogiannis et al., 2015).
These differences were detectable up to 10 years before the onset of AD symptoms. Finally, exosomal biomarkers of BIR were associated with higher brain atrophy in AD patients (Mullins et al., 2017) emphasizing the potential role of brain derived microvesicles as detectors of brain insulin signaling and biomarkers of brain damage due to metabolic and neurodegenerative disorders.
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