**1. Introduction**

Metabolic syndrome (MS) is a serious public health problem. It affects about 25% of the general population and, more alarmingly, around 40% of adults over 40 years old worldwide [1,2]. The definition of this syndrome has recently evolved to include a group of at least three of five cardio-metabolic abnormalities. These conditions include high blood pressure, central obesity, insulin resistance (IR), elevated blood triglycerides, and atherogenic dyslipidemia [3], which together lead to an increased risk of cardio-metabolic pathologies [4–6], as well as other diseases, such as arthritis [7] and some types of cancer [8].

**Citation:** Rojas, M.; Chávez-Castillo, M.; Pirela, D.; Parra, H.; Nava, M.; Chacín, M.; Angarita, L.; Añez, R.; Salazar, J.; Ortiz, R.; et al. Metabolic Syndrome: Is It Time to Add the Central Nervous System? *Nutrients* **2021**, *13*, 2254. https://doi.org/ 10.3390/nu13072254

Academic Editors: Omorogieva Ojo and Amanda Adegboye

Received: 21 May 2021 Accepted: 9 June 2021 Published: 30 June 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Likewise, the presence of MS-related disorders also plays a role in the pathophysiology of neurological disorders [9], reflecting the association between deficiencies in secretion and action of insulin and mild cognitive impairment (MCI) [10]. MCI is defined as cognitive dysfunction that exceeds what is typically expected for age and educational level but does not meet the criteria for a major neurocognitive disorder. General functionality is preserved in MCI [11] and it can be best described as an intermediate state between cognitive impairment characteristic of aging and major neurocognitive conditions, such as Alzheimer's disease (AD) [12,13].

Pathophysiological mechanisms of MCI have not been fully clarified. Thus, different hypotheses are proposed to explain the MCI/MS association [14]. A cyclical relationship seems to exist between IR and cognitive impairment, and the question of which phenomenon occurs first arises [15]. Additionally, if cognitive impairment precedes IR, it becomes a risk factor for developing MS. Therefore, this review briefly describes the history of MS and discusses clinical and preclinical findings that support the role of MS and IR as elements of pathophysiological mechanisms of cognitive impairment.

While most reviews on the topic focus on the MS-to-MCI relationship, this review goes beyond this by looking at the inverse relationship, examining available evidence regarding a new hypothesis that suggests that cognitive impairment could have a role in the development of IR and the appearance of MS. Among the mechanisms to be highlighted in this regard, the hyperphosphorylation of tau proteins and the formation of amyloid β (Aβ) plaques are proposed as alterations that go beyond the pathophysiology of Alzheimer's disease (AD), and their role in the pathophysiology of insulin alterations is examined.

#### **2. Metabolic Syndrome: Historical Aspects**

The first studies of MS started almost 100 years ago when Eskil Kylin, in 1921, and Gregorio Marañón, in 1922, independently published in the same journal (Zentralblatt für Innere Medizin) papers with the same title, "diabetes mellitus and hypertension" [16,17]. Yet, not until 1981 did Hanefeld and Leonhardt use the term "metabolic syndrome" for the first time [18].

In 1988, Gerald Reaven hypothesized that IR was a common etiological factor for a group of disorders he termed "Syndrome X" [19,20]. He used this name to emphasize its unknown origin. At this time, the fundamental pathophysiological role of IR was known. This mechanism had been studied by researchers, such as Randle [21]. In subsequent years, DeFronzo, Ferrannini, and others used the term "Insulin Resistance Syndrome", proposing that available evidence suggested its presence was the cause of MS [22].

The cause of MS and its components have been debated worldwide since the end of the 20th century. Many organizations, such as the World Health Organization (WHO) [23], the European Group for the Study of Insulin Resistance (EGIR) [24], the Adult Treatment Panel III (ATP-III) [25], the American Association of Clinical Endocrinologists (ACE/AACE) [26], and the International Diabetes Federation (IDF) [27], have proposed evolving diagnostic criteria. Some criteria have been progressively discarded and replaced with criteria that can be easily applied in daily clinical practice.

Finally, the IDF, the National Heart, Lung, and Blood Institute, the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association for the Study of Obesity made a joint statement in 2009 that concluded that a diagnosis of MS requires the presence of three or more of the following criteria: high abdominal circumference as defined for each geographical region, triacylglycerides (TAG) greater than or equal to 150 mg/dL, HDL levels less than 50 mg% in women or less than 40 mg% in men, systolic blood pressure (SBP) greater than or equal to 130 mmHg or diastolic blood pressure (DBP) greater than or equal to 85 mmHg, and glycemic levels greater than 100 mg/dL [3]. We now consider that the evolution of diagnostic criteria has reached a maturity level that makes it difficult to incorporate new criteria that are both easily recognized and provide useful clinical information [28]. IR continues to be the most

widely accepted hypothesis to describe MS pathophysiology that involves various organs and associations with numerous diseases [29].

#### **3. Mild Cognitive Impairment and Metabolic Syndrome: Molecular Basis**

Epidemiological, clinical, and experimental evidence provides a solid basis for the hypothesis that IR is the pathophysiological origin for dyslipidemias, high blood pressure, and disorders in glucose homeostasis [30]. As studies of MS continued, a relationship emerged between obesity, the syndrome's most prevalent individual criterion, and neurological alterations [31]. This association necessitates additional consideration of the pathophysiological mechanisms involved and how they are interconnected.

#### *3.1. From Metabolic Syndrome to Cognitive Impairment*

Epidemiological [32], neuroimaging [33], and animal modeling studies are available to characterize MS pathophysiology, accompanying diseases, and individual components in the development of neurodegenerative diseases and associated cognitive impairment [34]. The connection between diabetes mellitus (DM) and AD and the connection between obesity and cognitive impairment are two areas that have been investigated in depth, including reports of statistically significant relationships [10,35,36].

The hippocampus plays an important role in learning and memory. The effect of IR on hippocampal function has been widely studied [37]. Lindqvist et al. administered highand low-fat diets to different groups of rats, using bromodeoxyuridine (BrdU) to observe synaptogenesis after 4 weeks. Male rats fed the high-fat diet showed a significant decrease in neurogenesis in the hippocampus. The animals did not develop obesity [38]. This result could reflect the role of lipid alteration, a component of MS, in cognitive decline.

Karimi et al. studied long-term neuronal potentiation (LTP) in the dentate gyrus (DG) of the hippocampus in mice receiving different combinations of a high-fat diet and antioxidants. Mice fed a high-fat diet showed lower LTP levels compared with control animals. In contrast, mice that received antioxidants displayed elevated LTP [39]. These effects might be mediated by an increase in free radical production caused by the high-fat diet, leading to oxidative stress (OS). This hypothesis is supported by rescue of LTP levels through the administration of antioxidants [39].

#### 3.1.1. Role of IR in the Formation of Amyloid-Beta Plaques

Production of reactive oxygen species (ROS) results in increased levels of amyloid precursor peptide-β (AβPP) and increased expression and accumulation of amyloid-β 42 (Aβ) [40]. This accumulation leads to the formation of amyloid-beta plaques, identified as a key element of AD [41]. One pathway for increased ROS production is increased insulin levels that lead to changes in normal NADPH oxidase (NOX4) pathway function. Elevated insulin levels induce phosphoinositol-3 kinase (PI3K) to phosphorylate Rac instead of phosphatidylinositol bisphosphate (PIP2). This alteration increases NOX4 activity and ROS levels. This aberrant metabolism is perpetuated because elevated ROS leads to activation of casein kinase 2 (CK2) and consequent activation of the retromer. This action signals the degradation of glucose receptor, GLUT4, leading to a continued increase in glucose levels in the blood and, therefore, increased production of insulin [42] (Figure 1).

The metabolic syndrome (MS) and its components cause brain alterations such as neuroinflammation, hyperphosphorylation of Tau, formation of beta amyloid plaques, and vascular changes (not represented in the figure). This is achieved through changes in the signaling of hormones such as adiponectin, leptin, and insulin. These changes are clinically expressed as mild cognitive impairment (MCI), Alzheimer's disease (AD), and major vascular neurocognitive disorder.

**Figure 1.** Impact of metabolic syndrome on cognitive impairment. PIP2: phosphatidylinositol bisphosphate; AKT: protein kinase B; PI3K: phosphoinositide kinase-3; JNK: c-Jun N-terminal kinase; AGEs: advanced glycation end products; PP2A: protein phosphatase 2A; GSK3β: glycogen synthase kinase 3 beta; NOX4: NADPH oxidase 4; 02-: superoxide; H202: hydrogen peroxide; Aβ: amyloid beta. Solid lines mean activation; dashed lines mean inactivation.

This positive feedback produces an environment of neuronal inflammation, reported as a risk factor for AD. An associated hypothesis is that, along with neurofibrillary tangles and amyloid-beta plaques, inflammation has a critical role in the pathophysiology of the disease [43]. Insulin seems to play a significant role in the development of plaques, and hyperinsulinemia observed in IR leads to their formation. In vitro studies show that high levels of insulin affect the degradation and elimination of Aβ. Both insulin and Aβ are degraded by insulin-degrading enzyme (IDE). During hyperinsulinemia, IDE degrades insulin preferably to Aβ, promoting its oligomerization into insoluble aggregates [44]. In vivo experiments in rats corroborate these findings, showing that elimination of Aβ is reduced in the presence of high levels of insulin [45].

Insulin receptors provide an alternative explanation for IR effects on the hippocampus and other brain structures [46]. These receptors are abundant in metabolic active brain areas and exert their effects at the neuronal level via PI3K and mitogen-activated protein kinases (MAPK) pathways [47]. These pathways, when activated by insulin, promote angiogenesis in the brain. In the presence of IR, these pathways are not activated. This disruption might underlie the concomitant synaptic anomalies, memory disorders, decreases in neurogenesis at the hippocampus level, alterations in cognition, and decreases in levels of brain-derived neurotrophic factor (BDNF) [46].

#### 3.1.2. Metabolic Syndrome, Insulin Resistance, and Tau Proteins

Conversely, tau protein (TP) helps stabilize microtubules and its alteration results in the formation of neurofibrillary tangles [48]. Further, IR induces hyperphosphorylation of TP and induces cognitive impairment in human and animal models [49,50]. Thus, IR is associated with poorer performance on cognitive tests and higher levels of phosphorylated PT in cerebrospinal fluid (CSF) in cognitively normal individuals and carriers of the APOE allele ε4 [10,51].

One mechanism underlying this phenomenon involves glycogen synthase kinase-3β (GSK3β), a tau kinase regulated by insulin via the protein kinase B (AKT) pathway. Decreased brain insulin signaling caused by IR induces chronic exposure of neurons to high levels of insulin or an eventual decrease in insulin levels, resulting in PI3K dysfunction and reduced AKT-dependent phosphorylation. Downstream, GSK3β is activated, and ultimately TP is hyperphosphorylated [52,53]. The production of advanced glycation end products (AGEs) from OS damage via GSK3β receptors (RAGE) also increases the activity of GSK3β by an alternate pathway involving c-Jun N-terminal kinase (JNK) [54].

A recent study showed protein kinase A (PKA) is a potent tau kinase and its activation increases TP hyperphosphorylation in an insulin-deficient animal model [55]. Moreover, insulin deficiency influences hyperphosphorylated TP level by decreasing the activity of protein phosphatase 2 (PP2A) [56]. PP2A is the primary tau phosphatase involved in AD and its deregulation is associated with TP hyperphosphorylation [57]. Similarly, hypothermia, common in chronic DM, also leads to inhibition of PP2A activity [58].

Another pathological mechanism in AD is truncation of TP by proteolytic enzymes, such as caspases, peptidases, and thrombins that promote tau aggregation and formation of the central component of neurofibrillary tangles (NFT) [59]. DM stimulates apoptosis through the activation of caspases in affected tissues. Through hyperglycemia, DM might increase tau aggregation by activating caspases, thus contributing to AD risk [60]. Kim et al. demonstrated such increased tau aggregation in the brain of db/db rats using in vivo and in vitro type 2 diabetes mellitus (T2DM) animal models [61].

#### 3.1.3. Metabolic Syndrome, Leptin, Adiponectin, and Cognitive Disorders

Alterations in hormones involved in MS, such as leptin and adiponectin, are also linked to cognitive impairment [62]. Both hormones affect the metabolism of fatty acids and glucose as well as energy metabolism and food intake [63,64]. Their function in neuroplasticity, learning, and cognition [65,66] is now known via reports of leptin and adiponectin receptor expression in brain regions such as the hippocampus and neocortex [67].

Recent studies in animal models show that leptin deficiency or resistance is associated with cognitive disorders, such as reductions in LTP, long-term neuronal depression (LTD), and alterations in spatial memory [68]. Further, leptin modulates the production and elimination of Aβ in AD by inhibiting the formation of AβPP and increasing APOEε4-induced amyloid filament elimination. This activity may be mediated through the activation of AMP-activated protein kinase (AMPK) [69,70]. Leptin resistance in AD is associated with diminished activity in these pathways and increased cognitive impairment [71].

Additionally, adult rats deprived of adiponectin display several common characteristics of AD, including deposition of Aβ, TP phosphorylation, and neuroinflammation [72]. This observation is corroborated by Kim et al., who demonstrated that adiponectin receptor suppression also produced an AD-like phenotype [73] Thus, hormone deficiencies might be involved in AD pathogenesis. However, studies in humans are controversial since available information for the association of adiponectin and leptin levels in the blood and CSF with cognitive impairment is inconclusive [62].

#### 3.1.4. Metabolic Syndrome, Microvasculature, and Cognitive Impairment

Micro- and macrovascular changes observed in MS, such as hypertension and DM, are also associated with brain alterations, such as vascular neurocognitive disorder. However, several recent studies note the contribution of vascular risk factors in AD. Mechanisms for this accelerating cognitive decline are not fully elucidated [74].

Hypertension leads to alterations observed in magnetic resonance imaging (MRI), such as white matter lesions (WML), lacunar infarcts, microhemorrhages, and microinfarcts. All these abnormalities are part of a spectrum called small vessel cerebral disease (SVD), which is common in AD [75]. SVD is characterized by loss of smooth muscle cells in the mid-tunic, deposition of fibro-hyaline material, reduced light, and thickening of vascular walls [76]. Moss et al. studied Rhesus monkeys using an aortic coarctation model. Multiple microinfarcts and lesions in gray and white matter in hypertensive monkeys were associated with cognitive impairment [77]. Other mechanisms might involve large arteries via endothelial dysfunction that progresses to the formation of atherosclerotic plaques in the carotid or intracranial arteries. Such damage can cause ischemic events in brain regions related to cognition [78].

#### *3.2. Exploring the Inverse Relationship—From Cognitive Impairment to Metabolic Syndrome*

The consequences of MS on the development of cognitive impairment have been studied in depth [79], but the inverse relationship in which pathophysiological mechanisms of AD, such as hyperphosphorylation of TP and the formation of amyloid complexes-β, lead to the appearance of MS is largely unstudied.

#### 3.2.1. Tau Proteins and Deficits in Insulin Signaling

Interestingly, TPs, in addition to microtubule stabilization, also interact with insulin signaling pathway components in the brain. The N-terminal portion of TP can bind to homology 3 (SH3) domains of the Src family of tyrosine kinases, including domains of the p85 alpha subunit of PI3K, a key protein in the insulin signaling pathway. Under pathological conditions, hyperphosphorylation of TPs can lead to loss of functionality, triggering alterations in insulin signaling that eventually generate altered fasting glycemia and DM. The ability of TPs to interact with SH3 domains is inversely correlated with the degree of phosphorylation, suggesting that scaffolding properties of TPs are regulated by their phosphorylation status [80].

Further, co-immunoprecipitation studies of mouse brain tissue and N1E115 cells indicate that TPs bind to phosphatase and tensin homologous protein (PTEN), a negative insulin signal translocation regulator that catalyzes dephosphorylation of phosphatidylinositol triphosphate (PIP3) to PIP2. Thus, TP, by interacting with and inhibiting PTEN, promotes insulin signaling [81]. These studies raise the possibility that insulin helps maintain adequate brain activity due to TP and, conversely, pathological forms of TP could be harmful due to a loss of protein function. This suggestion is supported by a study that showed that TP removal was accompanied by loss of inhibitory effects of insulin on PTEN in the hippocampus, resulting in brain IR.

Concurrently, the absence of TP reduced the anorexigenic effect of insulin in the hypothalamus after intracerebroventricular injection of TP [81]. Previously, such injection induced increased food intake, weight gain, adiposity, hyperinsulinemia, and glucose intolerance in rodents with insulin receptor deletion in the hypothalamus [82,83]. These effects produce alterations in energy metabolism that may increase the risk of suffering from obesity, DM, and MS.

TP is also highly expressed in pancreatic islet β-cells. However, its function in peripheral tissues is not fully understood [84,85]. Wijesekara et al. investigated TP actions on β-cell function and glucose homeostasis using a tau KO rat model. Rats showed weight gain, defects in glucose signaling, and IR, leading to DM and ultimately MS. Thus, TP might be crucial for normal energy metabolism in peripheral tissues [86].

#### 3.2.2. Amyloid β and Insulinemic Alterations

In vitro and in vivo studies suggest that Aβ may also contribute to IR through various mechanisms. Aβ competitively inhibits the binding of insulin to its receptor [87] and activates the JAK2/STAT3/SOCS-1 signaling pathway to produce IR in the liver [88]. Further, the oligomer Aβ (AβO), a highly toxic species of Aβ, causes deregulation of N-methyl-D-aspartate (NMDA) receptors and leads to the production of excessive ROS. This effect is probably due to mitochondrial dysfunction [89].

This deregulation might lead to alterations in insulin signaling, since increased ROS activates several serine kinases, such as an inhibitor of the nuclear factor kappa-B kinase beta subunit (IKK-β), protein kinase C (PKC), and JNK. These kinases increase phosphorylation in Ser IRS-1 residues. ROS can cause OS and damage at mitochondrial and cellular

levels. This stress generates mitophagy and, at high levels of stress, apoptosis. The elimination of mitochondria by mitophagy results in a decrease in oxidation and consequent accumulation of lipids, leading to IR and T2DM [90].

Conversely, AβO causes a rapid and substantial loss of insulin receptors in dendrites and inhibition of insulin receptor autophosphorylation associated with NMDA activity [91]. Additionally, an increase in levels of IR markers p(Ser)-IRS-1 and p-JNK were observed in neurons after intracerebroventricular injection of AβO in vivo in monkeys [92].

#### 3.2.3. Amyloid β, Tau Protein, and Leptin

Aβ and TP have also been linked to alterations in leptin signaling. Bonda et al. showed that TP hyperphosphorylation leads to the formation of NFT and dysfunction in intracellular trafficking networks in the hippocampus. Thus, the leptin receptor in its long form (Ob-Rb) becomes unable to reach cell membranes, hindering its access to circulating free leptin and interrupting signaling. This activity might lead to increased food intake and weight gain with subsequent development of obesity and long-term MS [93]; leptin in the hippocampus is associated with regulating food intake and processing food-related memories [94].

Elevated levels of Aβ1-42 produced by beta-site amyloid cleaving enzyme 1 (BACE1) increase leptin resistance in the hypothalamus, which is associated with decreased sensitivity to exogenous leptin throughout the body and exacerbation of body weight gain in rats fed high-fat diets. Thus, countering BACE1 activity may be protective against metabolic disorders [95].

The above findings affirm cognitive impairment as a key trigger of alterations in insulin signaling in the hypothalamus. The latter region is the primary regulator of body weight via controlling food intake and peripheral metabolism [96]. Thus, cognitive impairment might lead to metabolic changes that precede the development of MS and its complications.

#### **4. Mild Cognitive Impairment and Metabolic Syndrome: Epidemiological Basis**

Evidence concerning the relationship of MS and its components with MCI has accumulated in the last few years to the point where grouping these disorders into a single clinical entity, the cognitive–metabolic syndrome, may be appropriate [97]. Below, we summarize clinical and epidemiological information on the MCI and MS relationship and its components.
