Revista Argentina de Clínica Psicológica 2020, Vol. XXIX, N°4, 969-980 DOI: 10.24205/03276716.2020.908 969

Memory deficit: adipose factors are new linkers?

Peng Ren, Bin Xiao, Qinghua Jin*

Abstract: and memory diseases are two major global health issues. Obesity is a risk factor for various diseases and increases the risk of AD and other related illnesses. Adipose tissue can secrete various biologically active adipokines, such as leptin, TNF-α, adiponectin, IL-6, PPAR-γ, etc. In recent years, studies have found that a variety of adipokines can affect the body's functions, regulate biological functions such as inflammation and immunity, and play an important role in memory-related diseases such as AD. This paper analyzes the mechanisms of several important fat factors involved in obesity and memory, and reviews the research progress of the biological pathways of obesity through fat factors to affect memory. Keywords: Obesity; adipokine; memory; biological pathway; research progress

Introduction Obesity has a global trend. With the improvement inflammatory response. Studies have shown that of people's living standards, the intake of high-fat the occurrence of obesity is often accompanied by diets has increased, leading to an increase in the abnormal secretion of adipokines, which can be incidence of overweight and obesity and related divided into pro-inflammatory factors, diseases year by year(Frederick etal.,2014). It is anti-inflammatory factors, and substances that exert estimated that more than 1.1 billion adults other regulatory effects according to their worldwide are overweight, of which 312 million are role(Fasshauer etal.,2016). Studies in recent years obese(Kassas,2015). Obesity has been recognized as have shown that overweight and obesity can lead to a chronic low-inflammatory state, and many major cognitive and neurobehavioral dysfunction, which is chronic diseases (such as cardiovascular diseases, manifested as a reduction in behavioral ability, diabetes, tumors, etc.) that threaten human health reduced attention and learning ability, and reduced are closely related to obesity. It is generally believed language comprehension(Freeman etal.,2013). that obesity is caused by abnormal or excessive Studies such as Underwood et al. (Underwood accumulation of adipose tissue in the etal.,2016; Underwood etal.,2016) showed that body(Arroyo-Johnson etal.,2016). As the most after 12 weeks of high-fat diet, male and female rats common tissue in the human body, adipose tissue in the new object recognition experiment and plays a vital role in the process of energy storage autonomous alternation experiment, the new object and endocrine function(Choe etal.,2016). Adipose discrimination index and autonomous alternation tissue is divided into yellow (white) adipose tissue score were significantly reduced, It shows that the and brown adipose tissue, which is mainly spatial memory ability that hippocampus depends composed of fat cells, immune cells, macrophages, on is impaired. Cognitive neurological studies have neutrophils and mast cells. Among them, fat cells used electroencephalogram scanning (EEG) to are important participants in the endocrine function perform working memory and continuous attention of adipose tissue, and are the dynamic and highly task tests on 158 overweight / obese female responsive units of adipose tissue, which coordinate adolescents, and found that overweight / obese girls the body's metabolic regulation(Maurizi etal.,2016; have the correct recognition rate in working Zelechowska etal.,2018). Adipokines usually refer to memory tasks than normal-weight girls of the same some hormones or small molecules secreted by age Lower(Bauer etal.,2016). Many existing studies various cells in adipose tissue, which can maintain have found that obese people may have working energy metabolism homeostasis through endocrine memory defects(Yang etal.,2018), adipokine is or paracrine pathways and participate in the body's closely related to the occurrence and development Department of Physiology and Pathophysiology, College of of cognitive disorders such as AD(Folch etal.,2015), Medicine, Yanbian University, but research in this field is still relatively lacking in Jilin,133000,China. *Corresponding Author:Qinghua Jin general, But its specific mechanism needs further Email:[email protected]. study. Therefore, this article reviews the biological

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 970 Peng Ren, Bin Xiao, Qinghua Jin ways in which obesity affects memory through fat same time resist the fat-promoting effect of insulin, factors, with a view to promoting related research. which in turn makes mice Reduced body mass. 1 Leptin However, in 2018, Celo et al. (Celo etal.,2018) found 1.1 Leptin and obesity that the effect of leptin on the human body is not The pro-inflammatory adipokine leptin is a product obvious. Obese patients have no significant change of the obesity gene (OB), and it was confirmed to be in body weight after using leptin, and only leptin is present in ob / ob mice by location cloning (Ozcan effective in patients with lipodystrophy. Except for etal.,2009). In 1994, Zhang et al. (Zhang obesity caused by congenital leptin deficiency, the etal.,2009)successfully cloned the homologous majority of obese people have elevated serum sequence of mouse obesity gene and human using leptin levels. Exogenous leptin administration has no site cloning technology. The sequence of significant effect on the appetite and weight of 84% of the two is the same. Injection of the protein obese patients. These results suggest that obese encoded by this gene can significantly improve the people may have central leptin resistance. To this obesity of mice. Obese phenotype, and then the end, researchers have proposed the role of leptin expression product of this obese gene was named resistance in obese patients, but so far, there is no leptin. Leptin is mainly encoded by obesity genes research and confirmation of the mechanism of and is a protein product secreted by white fat cells. leptin resistance at home and abroad. It can be It is rich in fat accumulation and can be detected in concluded that the effect of leptin in different placenta, ovary, skeletal muscle, breast epithelial populations will also be different. To play an active cells, bone marrow and lymphoid tissues. By its role in leptin in obese people, it is imperative to expression, leptin can regulate feeding behavior, and explore the mechanism of leptin resistance and seek lack of leptin can lead to overeating, obesity, and IR. ways to suppress leptin resistance Provide new Studies have found that it can regulate body mass ideas for solving the problem of obesity. through the central nervous system(Lin etal.,2018). 1.2 Leptin and memory The mechanism of action is mainly: (1) Leptin binds Hormones play an important regulatory role in many to the receptor and acts on the hypothalamic physiological and biochemical processes of the feeding regulation center, inhibiting the expression body(Celo etal.,2012). Brain-derived neurotrophic and secretion of mRNA of the arcuate neuropeptide factor (BDNF), a downstream target of leptin, is Y (NPY), which can increase muscle and sympathetic involved in the regulation of hypothalamic nerve excitation. Food intake and energy feeding(Rosas-Vargas etal.,2011), and abnormal lipid consumption are reduced, so inhibiting the metabolism is associated with neurodegenerative secretion of NPY can reduce appetite and increase diseases, especially Alzheimer's disease (AD). energy intake; in addition, obesity can cause Clinical studies have shown that diabetes patients hypothalamic endoplasmic reticulum stress, which have an increased risk of AD, suggesting that plays a central role in leptin resistance. (2) Act on endocrine diseases are associated with the nerve center, increase sympathetic nerve activity, neurodegenerative processes(Arab etal.,2011). The increase peripheral norepinephrine release, activate main feature of Alzheimer's disease is memory loss. fat cell membrane β3 receptors, increase decoupling The hippocampus plays an important basic role in protein synthesis, release stored energy in the form the process of learning and memory. Therefore, of heat energy, thereby increasing energy leptin has significant practical significance in consumption There are also studies showing that regulating the function of hippocampal neurons. leptin can inhibit the activity of fatty acyl-CoA Studies have shown that leptin is a key regulator of dehydrogenase and increase energy consumption by hippocampus function. Leptin plays an important consuming a large amount of fat and fatty role in regulating hippocampal synaptic plasticity acids(Cohen etal.,2002); (3) by increasing lipase and affecting glutamate receptors, mainly NMDA synthesis and reducing fatty acid synthase and and AMPA receptor transport (Moult etal.,2010), cytochrome C oxidase is produced to inhibit fat two The person is an important regulator of synthesis. In addition, energy consumption leads to neurological diseases such as learning and memory the expression of acetyl-CoA carboxylase gene, and epilepsy(Obeid etal.,2010; Moult etal.,2011; which can also directly inhibit fat synthesis. In 2016, Morley etal.,2010). In rodents deficient in leptin research by Petta et al. (Petta etal.,2016) confirmed receptors (OB-Rs), there are long-term potentiation that leptin can increase energy consumption, (LTP) and long-trem depression (LTD) defects in the oxidation of fatty acids, inhibit appetite and hippocampal CA1 area, and exogenous leptin is triacylglycerol synthesis in obese mice, and at the given Can not be reversed(Li,2015), NMDA

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 971 Peng Ren, Bin Xiao, Qinghua Jin receptor-dependent LTP in the hippocampal CA1 inflammation of adipose tissue, and ultimately region is the basis of spatial learning and memory, insulin resistance (IR). Influencing the expression, and found that these animals have abnormal activity and effects of TNF-α receptors provides an post-synaptic NMDA (n-methyl-D-aspartate) effective clinical treatment approach for the receptors in hippocampal CA1 neurons, The treatment of obesity-related IR(Tzanavari etal.,2010). activation of synaptic NMDA receptors increases In some rodent studies, it has been found that post-synaptic [Ca2+] i, which is crucial for synaptic administration of tumor necrosis factor alpha LTP induction in the hippocampal CA1 region. In the antibody can inhibit inflammatory activity, improve water maze experiment, the spatial memory ability fatty liver disease, and prevent diet-induced obesity of these animals was also impaired, suggesting that and insulin resistance(Gregor etal.,2011). TNF-α the decreased leptin effect may be related to stimulated cells and animal protein tyrosine abnormal leptin receptors. The role of leptin in phosphatase (PTP) 1B expression is up-regulated, regulating dendritic morphology is also important in and PTP1B expression is increased in obese and hippocampal synaptic plasticity and diabetic patients and animal peripheral tissues. neurodevelopment(Moult etal.,2010). OB-R is also -Drug treatment of alpha receptors can reduce expressed in cerebellar neurons, and leptin PTP1B and improve IR. TACE, also known as promotes this influx mediated by its NMDA receptor precursor protein processing enzymes (ADAM17), is NR2B. Leptin promotes increased synaptic a risk factor for IR and obesity. Increased TACE expression of AMPA receptors deficient in GluR2 in activity can increase the release of sTNF-α(Junyent hippocampal slices of adult rats, resulting in etal.,2010). Obese patients with type 2 diabetes increased persistence of excitatory synaptic have increased TACE activity in skeletal muscle transmission efficacy. The AMPA receptor lacking in tissue. Therefore, in the animal model of obesity IR, GluR2 can penetrate Ca2 +, leading to specific TACE is one of the main targets for the treatment of intracellular signaling pathways and / or required for IR. In addition, a TACE inhibitor, Mamastat, can synaptic efficacy. The above effects can partially improve insulin sensitivity and reverse lipid explain the beneficial effects of leptin on memory. production in obese mice induced by a high-sugar 2 Tumor necrosis factor-α(TNF-α) and high-fat diet(de etal.,2011). Inhibiting TNF-α by 2.1 TNF-α and obesity various means may improve IR, and in-depth Among the adipokines, there is a class of research on TNF-α inhibitory drugs for this idea is pro-inflammatory factors with various functional helpful for the treatment of obesity-related IR. In types-TNF-α. Human obesity is associated with contrast, there are also studies showing that TNF-α increased circulating TNF-α. Due to the large antibody treatment has no effect on human insulin amount of TNF-α expressed in fat tissues of obese sensitivity and obesity(Winer etal.,2011). A recent animals and humans, it is also considered to be an study showed that TNF-α antibody infliximab can adipokine, mainly derived from improve inflammation in obese, insulin-resistant mononuclear-macrophages in fat tissues. In 1993, healthy volunteers, but has no effect on insulin TNF-α was discovered in induced diabetes and resistance and endothelial function (Gonzalez-Gay obesity models, providing initial evidence for etal.,2010). establishing a link between inflammation and 2.2 TNF-α and memory obesity(Hotamisligil etal.,1993). The expression of AD patients have excessive expression of TNF-α in the serum of obese people is up-regulated, inflammatory cytokines such as TNF-α around Aβ and the level of TNF-α is reduced when the body plaques. At the same time, TNF-α levels have also weight is reduced. Inhibiting TNF-α in obese fa / fa been significantly increased in cerebrospinal fluid rats can significantly increase glucose uptake under and peripheral blood. Pathological processes such as the action of insulin in peripheral tissues. Knocking neuronal damage and degenerative diseases play an out the TNF-α gene in mice with diet-induced and important role. The possible mechanism of single-gene obesity models can significantly improve overexpression of TNF-α mediates AD neurotoxicity: insulin sensitivity(A,2017). TNF-α can stimulate fat First, it induces the activation of microglia and As in cells to release fatty acids, and free fatty acids will the cerebral cortex and hippocampus, producing strongly stimulate macrophages to produce TNF-α, excessive inflammatory factors and adhesion factors, which indicates that once metabolic inflammation resulting in neuroinflammatory lesions Aβ plaque begins, this vicious cycle caused by elevated TNF-α formation; the second is to induce increased will interfere with insulin signaling. Conduction and production of NO and free radicals, promote the energy metabolism, which causes systemic neurotoxicity of excitatory amino acids, leading to

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 972 Peng Ren, Bin Xiao, Qinghua Jin neuronal degeneration and death, and the model of secreted by normal white adipose tissue cells. This AD rats induced by fornix-hippocampal injury can secretion is susceptible to factors such as obesity. increase the inflammatory mediator TNF-α Causes Obese patients are significantly oxidative stress damage in the rat hippocampus, down-regulated(Xiao etal.,2009). The level is water maze training can increase the activity of negatively correlated (Gordon etal.,2009). At the SOD(Shema etal.,2007), has an antioxidant effect, is same time, Ouchi et al. (Ouchi etal.,2000) found that helpful to remove oxygen free radicals in blood and obesity reduces the expression of human brain tissue, reduce hippocampal neuron damage, adiponectin receptor 1 / human adiponectin protect hippocampal neurons , Maintain the receptor 2 and reduces the sensitivity of plasticity of cholinergic nerves; Third, it interacts adiponectin. Clinical studies have shown that the with TNF-α receptor to make TNF-α receptor bind to levels of adiponectin in patients with obesity, receptor binding protein, receptor acting protein hypertension, coronary heart disease, type 2 and Fas death domain binding protein, and induces diabetes, and MS are reduced, and reducing body of nerve cells; It directly acts on weight can significantly increase the body's endothelial cells, As and neurons, increases APP adiponectin levels. The spherical domain has a expression, and causes Aβ deposition. Aβ can higher biological activity than the full-length continue to activate microglia and overexpress the adiponectin, it can play a protective role in the inflammatory factors TNF-α and IL-1β, forming a body's metabolism, and it can improve insulin chronic inflammatory response in the brain of AD resistance, anti-atherosclerosis, suppress obesity, patients(Aisen,2008). Overexpression of TNF-α in suppress inflammation, and regulate bone the brain of AD patients induces neuronal toxicity formation. Biological functions such as tumor cascade, promotes neuronal damage and apoptosis, growth inhibition (Ramirez etal.,2014). Adiponectin and is highly related to Aβ plaque formation and is synthesized at high levels in adipocytes in lean neurodegenerative degeneration. And TNF-α gene organisms and is down-regulated in obesity-related polymorphism is significantly associated with the dysfunction adipocytes. Consistent with this concept, risk of AD. The study found that AD patients not only the expression of adiponectin can be suppressed by abnormally increased the frequency of TNF-α2 proinflammatory cytokines, hypoxia and oxidative alleles, but also those with TNF-α2 alleles had an stress, and is related to the adipose tissue earlier age of onset(Culpan etal.,2003); TNF-α gene environment of obese organisms(Arita etal.,1999). was detected at -308 in patients with delayed AD According to epidemiological data, adiponectin and There is a polymorphism at the site, the frequency insulin sensitivity are positively correlated during of TNF-α2 gene is significantly higher in the AD the development of obesity and diabetes. The group than in the control group(McCusker decrease of blood adiponectin concentration in type etal.,2001); TNF-α gene polymorphism affects 2 diabetes patients is related to body mass index transcription, and the transcription activity of and insulin sensitivity index, which is more obvious TNF-α2 is higher than that of TNF-α1, resulting in in obese patients. The experiment found that the TNF-α in Abnormally highly expressed in AD type of obesity is the main factor affecting the patients(Tarkowski etal.,2000). It can be speculated decline of serum adiponectin. The study observed that the increase of TNF-α gene polymorphism may that the level of serum adiponectin in patients with be caused by the expression of TNF-α in the brain of abdominal obesity decreased more than other patients with TNF-α gene polymorphism, which obesity types, which may be due to the difference aggravates neurodegeneration. Therefore, inhibition between the quantity and quality of adiponectin of TNF-α may be one of the mechanisms to improve expressed in adipose tissue in different parts, which the learning and memory function of AD model rats. can be inferred from Compared with other adipose Studies have also confirmed that trans-astaxanthin tissues, abdominal visceral fat may have a close can inhibit the expression of TNF-α, and then relationship with adiponectin. The study found that improve memory dysfunction caused by central there is no difference in adiponectin secreted by inflammation(Li,2015). subcutaneous adipose tissue of obese rats and 3 Adiponectin normal rats, but there is a large difference between 3.1 Adiponectin and obesity adiponectin secreted by abdominal adipose tissue, Adiponectin was discovered by Scherer in 1995 as a and the level of adiponectin in obese rats is lower cell-specific adipokine (Hu etal.,1996). Adiponectin's than normal In rats, visceral fat is considered to be gene is located on chromosome 3q27, usually the main tissue regulating serum adiponectin circulating in the blood at a high level, and is mainly metabolism. Adiponectin inhibits tumor growth by

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 973 Peng Ren, Bin Xiao, Qinghua Jin reducing angiogenesis, and adiponectin levels increases compensatoryly(Tvarijonaviciute increase with weight loss, suggesting that etal.,2013). Moreover, Kovacs et al. (56) tested the adiponectin may play an important role in the serum adiponectin in AD patients taking donepezil occurrence of obesity and related tumors, so and found that the serum adiponectin showed an adiponectin is considered to be related to obesity upward trend at the third month and significantly One of the potential tumor markers(Barb etal.,2007). increased at the sixth month (P <0.05), further Adiponectin is believed to reduce the confirm Increased levels of adiponectin have a incidence of in women, especially obese protective effect on patients with dementia. In women. Increasing the concentration of adiponectin, summary, adiponectin is a protective factor for increasing the expression of adiponectin receptors, dementia. Adiponectin levels in female dementia or developing adiponectin receptor stimulants and patients are increased, presumably affected by recombinant human adiponectin are all directions estrogen levels. Adiponectin may be involved in for the future treatment of female malignant tumors improving cognitive dysfunction by reducing the related to obesity. Recent studies have found that production and accumulation of Aβ, improving brain airway epithelial cells can also secrete energy supply, and protecting cells. adiponectin(Miller etal.,2009), and various cells in 4 Interleukin 6(IL-6) the lung have their receptors expressed(Sood 4.1 IL-6 and obesity etal.,2003); the levels of adiponectin in obese and Adipose tissue has the function of secreting patients are higher than in normal people cytokines, and 15% ~ 35% of the body's IL-6 content Decline(Arita etal.,1999; Ding etal.,2015). This is secreted by adipose tissue. It has recently been shows that adiponectin, as a specific lipogenic found that in obese patients with IR and obese type hormone, has a positive effect on the protection of 2 diabetic patients, the mRNA expression and metabolism and reducing the pressure of obesity. protein levels of IL-6 in adipose tissue and blood 3.2 Adiponectin and memory circulation concentration have increased, revealing According to the various physiological functions of that IL-6 in obese type 2 Diabetics may play a role. adiponectin, it is speculated that adiponectin is a The serum IL-6 level in obese patients is significantly protective factor for AD, but the recent research higher than that in normal people. Bastar et al. results are not the same as the inference. (Bastard etal.,2000)reported that serum IL-6 Kamogawa et al. (Kamogawa etal.,2010) found concentration in obese patients is related to some that low adiponectin levels are associated with signs of insulin resistance, such as BMI, waist dementia through a study of 517 community circumference, and fasting insulin concentration. members. And van Himbergen et al. (van Therefore, it is of great significance to detect the etal.,2012) concluded after 13 years of follow-up of serum IL-6 concentration in obese patients, and the 840 elderly people (541 women, median age 76 serum IL-6 level can be used as a marker of insulin years old), after adjusting for age, education level, resistance and endothelial dysfunction. APOEε4, body mass index, recent body mass Over-expressed IL-6 in obese bodies plays a central changes , Plasma DHA levels and other factors, it is role in IR. IR is one of the important features of type speculated that increased plasma adiponectin is an 2 diabetes. IL-6 may increase obesity. Type 2 independent risk factor for women with dementia diabetes IR may be caused by: ① accelerated fat or AD, and plasma insulin levels, blood glucose breakdown, leading to free fatty acid levels in levels and glycated hemoglobin levels are not patients Increase. Animal experiments have found statistically significant. However, it is currently that after neutralizing IL-6 with IL-6 antibody, not known that glucose metabolism disorders are only does insulin sensitivity increase, but plasma related to dementia(Chen etal.,2012), blood lipid free fatty acid levels also decrease, suggesting that metabolism disorders are related to the relationship between IL-6 and insulin action or dementia(Bales,2010), and the mainstream about IR may be adjusted by obesity , And partly by raising adiponectin has enhanced insulin sensitivity, free fatty acid levels(Kan etal.,2002). ②IL-6 has a anti-intimal hyperplasia, improved lipid metabolism down-regulating effect on glucose transporter 4 of and anti-hyperglycemia The effects are inconsistent adipocytes, and glucose transporter 4 is the and contradictory. Epidemiological investigations rate-limiting enzyme for glucose utilization in have shown that female patients have a longer peripheral tissues(Sandler etal.,1990). ③ IL-6 disease course than male patients. It is speculated produced by fat cells of obese type 2 diabetic that the level of adiponectin in female patients with patients inhibits the tyrosine kinase activity of dementia is affected by estrogen levels and insulin receptor of muscle tissue through endocrine

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 974 Peng Ren, Bin Xiao, Qinghua Jin and paracrine to reduce the effect of memory may be negatively correlated with age. Zhu insulin(Ornitz,2006). ④IL-6 can inhibit adiponectin et al. (Zhu etal.,2012) found that sleep gene expression and protein secretion. disturbances can lead to increased levels of IL-6 and 4.2 IL-6 and memory induce the activation of microglia in the Huang et al. (Huang etal.,2013) found that hippocampus. It is speculated that the activation of compared with the normal control group, fast-aging microglia may be the way of mice have decreased learning and memory and hippocampus-dependent learning and memory increased LTP. This seems to contradict the classic impairment after stress One. Jin et al. (Jin hypothesis that LTP is the basis of learning and etal.,2012) found that minocycline can improve memory, and its mechanism may be induced by LTP long-term memory impairment in elderly mice after to promote The release of inflammatory factor IL-6 surgery. This effect may be related to the increase of is increased, and IL-6 in turn inhibits LTP, impairing IL-6 and other cytokines caused by minocycline learning and memory, indicating that too much IL-6 inhibiting the activation of astrocytes. A may have a negative effect on learning and memory. study(Grassi-Oliveira etal.,2011) found that among Another clinical study(Kesler etal.,2013) found female patients with recurrent depression, those that the volume of hippocampus decreased, with poor immediate and delayed recall language memory decreased, and TNF-α and IL-6 performance had higher IL-6 levels, indicating that levels increased after in breast depression-related memory disorders may be cancer patients. It is speculated that this damage closely related to IL-6. Azevedo et al. (Azevedo may be mediated by TNF-α and IL-6. Braun et al. etal.,2013) showed that mice with ocular pial (Braun etal.,2013)found that the soluble gp130 meningeal amyloid lesions showed short-term protein specifically blocked the peripheral IL-6 signal memory impairment that may be related to transduction pathway of mice without affecting its increased levels of IL-6 and TNF-α and microglia classical IL-6 signal pathway. The mice in the activation. A recent study(Li etal.,2013) found that experimental group did not show hippocampal isoflurane-induced learning and memory dependence or non-hippocampus Dependent impairment is accompanied by increased levels of memory impairment indicates that the peripheral cytokines such as IL-6 and TNF-α, which may be IL-6 signal transduction pathway may not be closely related to glycogen synthase kinase-3β (GSK- 3β) related to memory, and the intracellular IL-6 signal mediated NF-κB acetylation is closely related. In transduction pathway in the experimental group addition, studies(del etal.,2013) have shown that may not be affected. Burton et al. (Burton the interaction of IL-6 with other cytokines (such as etal.,2012) found that IL-6 levels in the hippocampus TNF-α and IL-1β) and the formation of cytokine of mice injected with LPS and its STAT3 signaling networks play an important role in regulating LTP pathway were enhanced, and and learning and memory. hippocampus-dependent learning and memory 5 PPAR-γ were impaired. Intraventricular injection of soluble 5.1 PPAR-γ and obesity gp130 protein could completely block the above PPAR-γ is the main regulator of adipocyte gene changes. It shows that IL-6 signal transduction expression and signal transmission between insulin pathway in the central system may play a key role in cells. It is involved in the regulation of adipocyte infection-related hippocampus-dependent learning differentiation and lipid metabolism and is closely and memory impairment. Mitsuhashi et related to obesity. Some studies have pointed out al.(Mitsuhashi etal.,2013) found that that PPAR-γ has adipose tissue specificity and is macrophages induced by β-amyloid peptide (Aβ) induced before the transcription of many adipocyte increase the mRNA release of IL-6, IL-1 and TNF-α genes, which plays an important role in the with the increase of age, while Aβ is toxic Doctrine is differentiation of adipocytes.It may promote the one of the main doctrines of memory disorders in differentiation of adipocytes by regulating the AD diseases. It is speculated that IL-6 and other expression of downstream genes such as UNR. It cytokines may play a role in Aβ-related memory also regulates the down-regulation of AP15 and disorders. Studies have found that excessive IL-1β other genes to increase the number of apoptotic and IL-6 in monocytes of older persons may indicate cells during differentiation, thereby regulating the impaired working memory(Simpson etal.,2013), differentiation of adipocytes. After activated by its and IL-6 in prospective memory is negatively ligand, PPAR-γ binds to the retinoid receptor α correlated with age(Lekander etal.,2011), (RXRα) to form a heterodimer, and then binds to a indicating IL-6 in working memory and prospective specific DNA sequence (this sequence is called the

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 975 Peng Ren, Bin Xiao, Qinghua Jin peroxisome proliferator response element, or PPRE) , acid absorption-related genes in adipose tissue, Regulate the transcription of target genes, and such as lipoprotein lipase, fatty acid transporter and eventually lead to the formation of adipocytes. fatty acyl-CoA synthetase genes, but does not Among the three subtypes, only PPAR-γ2 is change the expression of these genes in muscle specifically expressed by adipose tissue. Therefore, tissue. This leads to a relative loss of fatty acids in PPAR-γ2 is particularly important in the process of muscle tissue. However, the Pro12Ala polymorphism adipose tissue differentiation. The 115th amino acid of the PPAR-γ gene exacerbates dyslipidemia in of PPAR-γ2 changed, which led to the continuous obese type 2 diabetes patients, resulting in activation of PPAR-γ and accelerated differentiation increased serum TC and non-HDL-C(Ahluwalia of fat cells. The patient showed severe obesity, but etal.,2002), which may be related to the not accompanied by insulin resistance. PPAR-γ2 downregulation of PPAR-γ transcription by Pro12Ala heterozygous mice or humans carrying A alleles can mutation. prevent insulin resistance and high-fat diet-induced 5.2 PPAR-γ and memory obesity due to decreased PPAR-γ2 activity, Helisalmi et al. (Helisalmi etal.,2008) analyzed 8 SNP decreased leptin levels, increased FFA oxidation, and sites of PPAR-γ gene for 538 AD patients in Finland reduced fat production(Kadowaki,2001). Similarly, if and 672 controls, and compared the distribution of PPAR-γ antagonists are used, they can improve single alleles and genotypes and estimated the obesity and insulin resistance. PPAR-γ can directly singles between cases and controls. Body shape activate fatty acid binding protein 2, frequency. In the haplotype analysis of single SNP phosphoenolpyruvate carboxykinase at the and PPAR-γ genes between the study groups, there transcriptional level, and enable the expression of was no significant difference in AD risk. It is many genes in adipocytes, thereby promoting the concluded that the PPAR-γ gene does not play a differentiation of preadipocytes and non-adipocytes major role in the genetic susceptibility to AD in the into adipocytes. PPAR-γ can promote adipocyte Finnish population. Shibata N et al. (Shibata differentiation, increase its number but decrease its etal.,2013) genotyped rs1801282 and rs3856806 volume, increase the number of insulin receptors on exon SNPs of the two groups of PPAR-γ gene in 171 the adipocyte membrane, and inhibit the AD patients and 136 age-matched controls as the hypertrophy of adipocytes, reduce FFA, and research subjects, and concluded that these two up-regulate the expression of adiponectin(Szaniszlo SNPs did not affect AD risk of Japanese population. etal.,2009). The loss of PPAR-γ target in adipose Although most studies suggest that PPAR-γ gene tissue significantly reduces the generation of polymorphism is not significantly associated with adipocytes and makes them hypertrophy, and the the risk of AD susceptibility, some scholars have hypertrophy of adipocytes can increase plasma FFA found through follow-up studies that PPAR-γ and TG, and reduce leptin and ACRP30(He Ala12-478T genotype carriers have a significantly etal.,2003). The study found that PPAR-γ knockout younger age of onset dementia than non-carriers (P heterozygous mice and KKA (y) using PPAR-γ = 0.026), indicating that the PPAR-γ gene may antagonists can protect fat cells from hypertrophy change the age of onset of late-onset AD (Koivisto and insulin resistance caused by a high-fat etal.,2006). A study of the Pro12Ala polymorphism diet(Kamon etal.,2003). It can be seen that PPAR-γ of gene exon 2 in samples from patients with positively regulates the differentiation of adipocytes, late-onset AD found that compared with the control and inhibiting PPAR-γ can block the differentiation group, the proportion of Ala genotypes was effect of adipocytes. In addition to playing a key role significantly higher in patients over 80 years old (P = in adipocyte differentiation, PPAR-γ also plays an 0.034), and those over 80 years old The risk of AD in important role in mediating fatty acid oxidation and the population carrying the Ala allele increased by lipid metabolism. PPAR-γ is highly expressed in nearly 2-fold (OR = 1.98; 95% CI: 1.03-3.80, P = 0.04). adipocytes, especially in the differentiation phase, The results of the study indicate that the PPAR-γ and many genes involved in fatty acid transport and gene may affect the susceptibility of late-onset AD metabolism are regulated by PPAR-γ at the over 80 years of age(Scacchi etal.,2007). Further transcription level. PPAR-γ can regulate all aspects of investigation found that the plasma sRAGE level of fatty acid metabolism, increase the expression of AD patients with Pro / Ala genotype was fatty acid transporters and fatty acid transport significantly lower than that of Pro / Pro genotype enzymes, and stimulate cellular intake of fatty acids patients. These findings suggest that the functional and conversion to fatty acyl CoA(Kamon etal.,1998). PPAR-γ Pro12Ala polymorphism may change the age PPAR-γ can selectively induce the expression of fatty of onset of AD(Yao etal.,2009). In addition, there is a

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 976 Peng Ren, Bin Xiao, Qinghua Jin gene-gene interaction between the PPAR-γ gene and America.45(4):571-9" the susceptibility genes of AD, and a Bauer LO, Manning KJ. Challenges in the Detection gene-environment interaction with the risk factors of Working Memory and Attention Decrements of AD, so that its carriers have a higher AD risk than among Overweight Adolescent Girls. the control group(Zhang etal.,2017) . Neuropsychobiology. 6 Conclusion 2016;73(1):43-51.PMID:26812684" At present, the relationship between obesity and AD Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose and other related diseases has gradually become a Tissue Remodeling: Its Role in Energy research hotspot at home and abroad. Obesity is a Metabolism and Metabolic Disorders. Frontiers complex chronic metabolic disease that has become in endocrinology. 2016;7:30.PMID:27148161" a global problem for humans. Studies have shown Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, that obese patients caused by a long-term high-fat Liedtke W, Soukas AA, et al. Role for diet may appear Problems such as amnesia and stearoyl-CoA desaturase-1 in leptin-mediated cognitive dysfunction, obesity is an important risk weight loss. Science (New York, NY). factor for the development of Alzheimer's 2002;297(5579):240-3.PMID:12114623" disease(Kanoski etal.,2011). Epidemiological data Fasshauer M, Blüher M. Adipokines in health and show that patients with chronic overweight or disease. Trends in Pharmacological obesity have a significantly higher chance of Sciences.36(7):461-70" suffering from Alzheimer ’s disease than normal Folch J, Patraca I, Martinez N, Pedros I, Petrov D, people. The proportion of people who are Ettcheto M, et al. The role of leptin in the overweight from middle age to old age are more sporadic form of Alzheimer's disease. likely to suffer from dementia than those with Interactions with the adipokines amylin, ghrelin normal weight.35 %(Profenno etal.,2010; Kalmijn and the pituitary hormone prolactin. Life etal.,2004; Kanoski etal.,2007). Since the discovery sciences. 2015;140:19-28.PMID:25998028" of adipokines, there has been a new understanding Freeman LR, Zhang L, Nair A, Dasuri K, Francis J, of the study of adipokines and the pathogenesis of Fernandez-Kim SO, et al. Obesity increases memory diseases. Epidemiology and in vitro cerebrocortical and experiments have confirmed that a variety of fat impairs brain function. Free radical biology & factors leptin, TNF-α, adiponectin, IL-6, PPAR-γ are medicine. 2013;56:226-33.PMID:23116605" closely related to obesity and memory, and are Maurizi G, Babini L, Della Guardia L. Potential role of closely related to the occurrence and development microRNAs in the regulation of adipocytes of memory-related diseases such as AD Correlation. liposecretion and adipose tissue physiology. The incidence of memory diseases such as AD is Journal of cellular physiology. increasing year by year, which is of great harm, as 2018;233(12):9077-86.PMID:29932216" well as the diversity of fat factors, the complexity of Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, et al. the regulatory network and the heterogeneity of Endoplasmic reticulum stress plays a central different target cells, making fat factors related to role in development of leptin resistance. Cell obesity and memory diseases The mechanism still metabolism. 2009;9(1):35-51.PMID:19117545" needs in-depth research and exploration. Taking Zelechowska P, Kozlowska E, Pastwinska J, Agier J, adipokines as new targets and conducting more Brzezinska-Blaszczyk E. Adipocytokine in-depth basic and clinical research can further Involvement in Innate Immune Mechanisms. J clarify the mechanism of memory diseases and Interferon Cytokine Res. 2018.PMID:30431386" provide new ideas for the prevention and treatment Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, of such diseases. Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. Acknowledgement 1994;372(6505):425-32.PMID:7984236" This paper is supported by National Natural Science Yang Y, Shields GS, Guo C, Liu Y. Executive function Foundation of China(No.81760158); and National performance in obesity and overweight key research and development individuals: A meta-analysis and review. projects(No.2018YFF0300405). Neuroscience and biobehavioral reviews. 2018;84:225-44.PMID:29203421" References A. SS. Lipid-induced insulin resistance mediated by Arroyo-Johnson C, Mincey KD. Obesity Epidemiology the proinflammatory receptor TLR4 requires Worldwide. Gastroenterology Clinics of North saturated fatty acid–induced ceramide

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 977 Peng Ren, Bin Xiao, Qinghua Jin biosynthesis in mice. Journal of Clinical trans-signaling in the senescent mouse brain is Investigation.121(5):1858-70 involved in infection-related deficits in Ahluwalia M, Evans M, Morris K, Currie C, Davies S, contextual fear conditioning. Brain, behavior, Rees A, et al. The influence of the Pro12Ala and immunity. mutation of the PPAR-gamma receptor gene on 2012;26(5):732-8.PMID:22062497 metabolic and clinical characteristics in Celo E, Kalari B, Toti F. A YOUNG ADULT WITH treatment-naive patients with type 2 diabetes. GENERALIZED LIPODYSTROPHY AND DIABETES Diabetes, obesity & metabolism. MELLITUS (CASE REPORT). Georgian medical 2002;4(6):376-8.PMID:12406034 news. 2018(277):27-31.PMID:29745909 Aisen PS. The inflammatory hypothesis of Alzheimer Chen RH, Jiang XZ, Zhao XH, Qin YL, Gu Z, Gu PL, et disease: dead or alive? Alzheimer disease and al. Risk factors of mild cognitive impairment in associated disorders. middle aged patients with type 2 diabetes: a 2008;22(1):4-5.PMID:18317241 cross-section study. Annales d'endocrinologie. Arab L, Sadeghi R, Walker DG, Lue LF, Sabbagh MN. 2012;73(3):208-12.PMID:22704263 Consequences of Aberrant Insulin Regulation in the Culpan D, MacGowan SH, Ford JM, Nicoll JA, Griffin Brain: Can Treating Diabetes be Effective for WS, Dewar D, et al. Tumour necrosis Alzheimer's Disease. Current factor-alpha gene polymorphisms and neuropharmacology. Alzheimer's disease. Neurosci Lett. 2011;9(4):693-705.PMID:22654727 2003;350(1):61-5.PMID:12962917 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, de Meijer VE, Le HD, Meisel JA, Sharma AK, Popov Y, Miyagawa J, et al. Paradoxical decrease of an Puder M. Tumor necrosis factor adipose-specific protein, adiponectin, in obesity. alpha-converting enzyme inhibition reverses Biochemical and biophysical research hepatic steatosis and improves insulin communications. sensitivity markers and surgical outcome in 1999;257(1):79-83.PMID:10092513 mice. PloS one. Azevedo EP, Ledo JH, Barbosa G, Sobrinho M, Diniz L, 2011;6(9):e25587.PMID:21980496 Fonseca AC, et al. Activated microglia mediate del Rey A, Balschun D, Wetzel W, Randolf A, synapse loss and short-term memory deficits in Besedovsky HO. A cytokine network involving a mouse model of transthyretin-related brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and oculoleptomeningeal amyloidosis. Cell death & TNFalpha operates during long-term disease. 2013;4:e789.PMID:24008733 potentiation and learning. Brain, behavior, and Bales KR. Brain lipid metabolism, apolipoprotein E immunity. 2013;33:15-23.PMID:23747799 and the pathophysiology of Alzheimer's disease. Desvergne B, A IJ, Devchand PR, Wahli W. The Neuropharmacology. peroxisome proliferator-activated receptors at 2010;59(4-5):295-302.PMID:20079752 the cross-road of diet and hormonal signalling. Barb D, Williams CJ, Neuwirth AK, Mantzoros CS. The Journal of steroid biochemistry and Adiponectin in relation to malignancies: a molecular biology. review of existing basic research and clinical 1998;65(1-6):65-74.PMID:9699859 evidence. The American journal of clinical Ding Y, Yang H, He H, Shi H, He P, Yan S, et al. Plasma nutrition. 2007;86(3):s858-66.PMID:18265479 Adiponectin Concentrations and Adiponectin Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Gene Polymorphisms Are Associated with Laville M, et al. Elevated levels of interleukin 6 Bronchial Asthma in the Chinese Li Population. are reduced in serum and subcutaneous Iranian journal of allergy, asthma, and adipose tissue of obese women after weight immunology. 2015;14(3):292-7.PMID:26546898 loss. J Clin Endocrinol Metab. Fernandez AM, Torres-Aleman I. The many faces of 2000;85(9):3338-42.PMID:10999830 insulin-like peptide signalling in the brain. Braun O, Dewitz C, Moller-Hackbarth K, Scheller J, Nature reviews Neuroscience. Schiffelholz T, Baier PC, et al. Effects of 2012;13(4):225-39.PMID:22430016 blockade of peripheral interleukin-6 Frederick CB, Snellman K, Putnam RD. Increasing trans-signaling on hippocampus-dependent socioeconomic disparities in adolescent obesity. and independent memory in mice. J Interferon Proc Natl Acad Sci U S A. 2014;111(4):1338-42 Cytokine Res. Gonzalez-Gay MA, Gonzalez-Juanatey C, 2013;33(5):254-60.PMID:23215755 Vazquez-Rodriguez TR, Miranda-Filloy JA, Llorca Burton MD, Johnson RW. Interleukin-6 J. Insulin resistance in rheumatoid arthritis: the

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 978 Peng Ren, Bin Xiao, Qinghua Jin impact of the anti-TNF-alpha therapy. Annals of Drugs and Diet Network study. Nutrition, the New York Academy of Sciences. metabolism, and cardiovascular diseases : 2010;1193:153-9.PMID:20398022 NMCD. 2010;20(10):698-705.PMID:19819120 Gordon ME, McKeever KH, Betros CL, Manso Filho Kadowaki T. [PPAR gamma agonist and antagonist]. HC. Plasma leptin, ghrelin and adiponectin Nihon yakurigaku zasshi Folia pharmacologica concentrations in young fit racehorses versus Japonica. 2001;118(5):321-6.PMID:11729635 mature unfit standardbreds. Veterinary journal Kalmijn S, van Boxtel MP, Ocke M, Verschuren WM, (London, England : 1997). Kromhout D, Launer LJ. Dietary intake of fatty 2007;173(1):91-100.PMID:16377220 acids and fish in relation to cognitive Grassi-Oliveira R, Bauer ME, Pezzi JC, Teixeira AL, performance at middle age. Neurology. Brietzke E. Interleukin-6 and verbal memory in 2004;62(2):275-80.PMID:14745067 recurrent major depressive disorder. Neuro Kamogawa K, Kohara K, Tabara Y, Uetani E, Nagai T, endocrinology letters. Yamamoto M, et al. Abdominal fat, 2011;32(4):540-4.PMID:21876502 adipose-derived hormones and mild cognitive Gregor MF, Hotamisligil GS. Inflammatory impairment: the J-SHIPP study. Dementia and mechanisms in obesity. Annual review of geriatric cognitive disorders. immunology. 2011;29:415-45.PMID:21219177 2010;30(5):432-9.PMID:21088422 He W, Barak Y, Hevener A, Olson P, Liao D, Le J, et al. Kamon J, Yamauchi T, Terauchi Y, Kubota N, Adipose-specific peroxisome Kadowaki T. [The mechanisms by which proliferator-activated receptor gamma PPARgamma and adiponectin regulate glucose knockout causes insulin resistance in fat and and lipid metabolism]. Nihon yakurigaku zasshi liver but not in muscle. Proc Natl Acad Sci U S A. Folia pharmacologica Japonica. 2003;100(26):15712-7.PMID:14660788 2003;122(4):294-300.PMID:14501164 Helisalmi S, Tarvainen T, Vepsalainen S, Koivisto AM, Kan SH, Elanko N, Johnson D, Cornejo-Roldan L, Hiltunen M, Soininen H. Lack of genetic Cook J, Reich EW, et al. Genomic screening of association between PPARG gene fibroblast growth-factor receptor 2 reveals a polymorphisms and Finnish late-onset wide spectrum of mutations in patients with Alzheimer's disease. Neurosci Lett. syndromic craniosynostosis. American journal 2008;441(2):233-6.PMID:18573313 of human genetics. Hotamisligil GS, Shargill NS, Spiegelman BM. 2002;70(2):472-86.PMID:11781872 Adipose expression of tumor necrosis Kanoski SE, Davidson TL. Western diet consumption factor-alpha: direct role in obesity-linked and cognitive impairment: links to hippocampal insulin resistance. Science (New York, NY). dysfunction and obesity. Physiology & behavior. 1993;259(5091):87-91.PMID:7678183 2011;103(1):59-68.PMID:21167850 Hu E, Liang P, Spiegelman BM. AdipoQ is a novel Kanoski SE, Meisel RL, Mullins AJ, Davidson TL. The adipose-specific gene dysregulated in obesity. effects of energy-rich diets on discrimination The Journal of biological chemistry. reversal learning and on BDNF in the 1996;271(18):10697-703.PMID:8631877 hippocampus and prefrontal cortex of the rat. Huang Y, Hu Z, Liu G, Zhou W, Zhang Y. Cytokines Behav Brain Res. induced by long-term potentiation (LTP) 2007;182(1):57-66.PMID:17590450 recording: a potential explanation for the lack Kassas HMKI. Cardio Metabolic Syndrome: A Global of correspondence between learning/memory Epidemic. Journal of Diabetes & Metabolism. performance and LTP. Neuroscience. 2015;06(3) 2013;231:432-43.PMID:23201254 Kesler S, Janelsins M, Koovakkattu D, Palesh O, Jin WJ, Feng SW, Feng Z, Lu SM, Qi T, Qian YN. Mustian K, Morrow G, et al. Reduced Minocycline improves postoperative cognitive hippocampal volume and verbal memory impairment in aged mice by inhibiting performance associated with interleukin-6 and astrocytic activation. Neuroreport. tumor necrosis factor-alpha levels in 2014;25(1):1-6.PMID:24247278 chemotherapy-treated breast cancer survivors. Junyent M, Parnell LD, Lai CQ, Arnett DK, Tsai MY, Brain, behavior, and immunity. 2013;30 Kabagambe EK, et al. ADAM17_i33708A>G Suppl:S109-16.PMID:22698992 polymorphism interacts with dietary n-6 Koivisto AM, Helisalmi S, Pihlajamaki J, Hiltunen M, polyunsaturated fatty acids to modulate Koivisto K, Moilanen L, et al. Association obesity risk in the Genetics of Lipid Lowering analysis of peroxisome proliferator-activated

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 979 Peng Ren, Bin Xiao, Qinghua Jin receptor gamma polymorphisms and late onset Morley JE, Banks WA. Lipids and cognition. Journal Alzheimer's disease in the Finnish population. of Alzheimer's disease : JAD. Dementia and geriatric cognitive disorders. 2010;20(3):737-47.PMID:20413879 2006;22(5-6):449-53.PMID:16988505 Moult PR, Cross A, Santos SD, Carvalho AL, Lindsay Y, Lekander M, von Essen J, Schultzberg M, Connolly CN, et al. Leptin regulates AMPA Andreasson AN, Garlind A, Hansson LO, et al. receptor trafficking via PTEN inhibition. The Cytokines and memory across the mature life Journal of neuroscience : the official journal of span of women. Scandinavian journal of the Society for Neuroscience. psychology. 2011;52(3):229-35.PMID:21332483 2010;30(11):4088-101.PMID:20237279 Li J, Xia Y, Liu T, Wang J, Dai W, Wang F, et al. Moult PR, Harvey J. NMDA receptor subunit Protective effects of astaxanthin on composition determines the polarity of ConA-induced autoimmune hepatitis by the leptin-induced synaptic plasticity. JNK/p-JNK pathway-mediated inhibition of Neuropharmacology. autophagy and apoptosis. PloS one. 2011;61(5-6):924-36.PMID:21752339 2015;10(3):e0120440.PMID:25761053 Obeid M, Frank J, Medina M, Finckbone V, Bliss R, Li SY, Chen X, Chen YL, Tan L, Zhao YL, Wang JT, et al. Bista B, et al. Neuroprotective effects of leptin Role of GSK-3beta in isoflurane-induced following kainic acid-induced status epilepticus. neuroinflammation and cognitive dysfunction Epilepsy & behavior : E&B. in aged rats. Journal of Huazhong University of 2010;19(3):278-83.PMID:20817614 Science and Technology Medical sciences = Hua Ornitz DM. MODEL FOR THE PHARMACOLOGIC zhong ke ji da xue xue bao Yi xue Ying De wen TREATMENT OF CROUZON SYNDROME. ban = Huazhong keji daxue xuebao Yixue Neurosurgery. 2006(1):1 Yingdewen ban. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, 2013;33(4):530-5.PMID:23904373 Kuriyama H, et al. Adiponectin, an Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. adipocyte-derived plasma protein, inhibits Impairment of long-term potentiation and endothelial NF-kappaB signaling through a spatial memory in leptin receptor-deficient cAMP-dependent pathway. Circulation. rodents. Neuroscience.113(3):0-615 2000;102(11):1296-301.PMID:10982546 Lin TC, Huang KW, Liu CW, Chang YC, Lin WM, Yang Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa TY, et al. Leptin signaling axis specifically P, Miele L, et al. Pathophysiology of Non associates with clinical prognosis and is Alcoholic Fatty Liver Disease. Int J Mol Sci. multifunctional in regulating cancer 2016;17(12).PMID:27973438 progression. Oncotarget. Profenno LA, Porsteinsson AP, Faraone SV. 2018;9(24):17210-9.PMID:29682217 Meta-analysis of Alzheimer's disease risk with McCusker SM, Curran MD, Dynan KB, McCullagh CD, obesity, diabetes, and related disorders. Biol Urquhart DD, Middleton D, et al. Association Psychiatry. 2010;67(6):505-12.PMID:19358976 between polymorphism in regulatory region of Ramirez VI, Miller E, Meireles CL, Gelfond J, gene encoding tumour necrosis factor alpha Krummel DA, Powell TL. Adiponectin and and risk of Alzheimer's disease and vascular IGFBP-1 in the development of gestational dementia: a case-control study. Lancet. diabetes in obese mothers. BMJ open diabetes 2001;357(9254):436-9.PMID:11273064 research & care. Miller M, Cho JY, Pham A, Ramsdell J, Broide DH. 2014;2(1):e000010.PMID:25452858 Adiponectin and functional adiponectin Rosas-Vargas H, Martinez-Ezquerro JD, Bienvenu T. receptor 1 are expressed by airway epithelial Brain-derived neurotrophic factor, food intake cells in chronic obstructive pulmonary disease. regulation, and obesity. Archives of medical Journal of immunology (Baltimore, Md : 1950). research. 2011;42(6):482-94.PMID:21945389 2009;182(1):684-91.PMID:19109202 Sandler S, Bendtzen K, Eizirik DL, Welsh M. Mitsuhashi M, Taub DD, Kapogiannis D, Eitan E, Interleukin-6 affects insulin secretion and Zukley L, Mattson MP, et al. Aging enhances glucose metabolism of rat pancreatic islets in release of exosomal cytokine mRNAs by vitro. Endocrinology. Abeta1-42-stimulated macrophages. FASEB 1990;126(2):1288-94.PMID:2404746 journal : official publication of the Federation Scacchi R, Pinto A, Gambina G, Rosano A, Corbo RM. of American Societies for Experimental Biology. The peroxisome proliferator-activated receptor 2013;27(12):5141-50.PMID:24014820 gamma (PPAR-γ2) Pro12Ala polymorphism is

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA 980 Peng Ren, Bin Xiao, Qinghua Jin associated with higher risk for Alzheimer's Impairment in Hippocampal Memory and disease in octogenarians. Brain research. Sex-Dependent Alterations in Peripheral 2007;1139(1):1-5 Metabolism. Neural plasticity. Shema R, Sacktor TC, Dudai Y. Rapid erasure of 2016;2016:7385314.PMID:26819773 long-term memory associations in the cortex by Underwood EL, Thompson LT. High-fat diet impairs an inhibitor of PKM zeta. Science (New York, spatial memory and hippocampal intrinsic NY). 2007;317(5840):951-3.PMID:17702943 excitability and sex-dependently alters Shibata N, Motoi Y, Tomiyama H, Ohnuma T, circulating insulin and hippocampal insulin Kuerban B, Tomson K, et al. Lack of Genetic sensitivity. Biology of sex differences. Associations of PPAR-gamma and PGC-1alpha 2016;7:9.PMID:26823968 with Alzheimer's Disease and Parkinson's van Himbergen TM, Beiser AS, Ai M, Seshadri S, Disease with Dementia. Dementia and geriatric Otokozawa S, Au R, et al. Biomarkers for insulin cognitive disorders extra. resistance and inflammation and the risk for 2013;3(1):161-7.PMID:23741228 all-cause dementia and alzheimer disease: Simpson EE, Hodkinson CF, Maylor EA, McCormack results from the Framingham Heart Study. JM, Rae G, Strain S, et al. Intracellular cytokine Archives of neurology. production and cognition in healthy older 2012;69(5):594-600.PMID:22213409 adults. Psychoneuroendocrinology. Winer DA, Winer S, Shen L, Wadia PP, Yantha J, 2013;38(10):2196-208.PMID:23664267 Paltser G, et al. B cells promote insulin Sood A, Shore SA. Adiponectin, Leptin, and Resistin resistance through modulation of T cells and in Asthma: Basic Mechanisms through Population production of pathogenic IgG antibodies. Studies. Journal of allergy. Nature medicine. 2013;2013:785835.PMID:24288549 2011;17(5):610-7.PMID:21499269 Szaniszlo P, German P, Hajas G, Saenz DN, Xiao N, Yin M, Zhang L, Qu X, Du H, Sun X, et al. Woodberry MW, Kruzel ML, et al. Effects of Tumor necrosis factor-alpha deficiency retards Colostrinin on gene expression-transcriptomal early fatty-streak lesion by influencing the network analysis. Int Immunopharmacol. expression of inflammatory factors in apoE-null 2009;9(2):181-93.PMID:19015048 mice. Molecular genetics and metabolism. Tarkowski E, Liljeroth AM, Nilsson A, Ricksten A, 2009;96(4):239-44.PMID:19157944 Davidsson P, Minthon L, et al. TNF gene Yao L, Li K, Zhang L, Yao S, Piao Z, Song L. Influence polymorphism and its relation to intracerebral of the Pro12Ala polymorphism of PPAR-gamma production of TNFalpha and TNFbeta in AD. on age at onset and sRAGE levels in Alzheimer's Neurology. disease. Brain research. 2000;54(11):2077-81.PMID:10851366 2009;1291:133-9.PMID:19631630 Tvarijonaviciute A, Carrillo-Sanchez JD, Ceron JJ. Zhang H, Zheng W, Hua L, Wang Y, Li J, Bai H, et al. Effect of estradiol and progesterone on Interaction between PPAR gamma and SORL1 metabolic biomarkers in healthy bitches. gene with Late-Onset Alzheimer's disease in Reproduction in domestic animals = Chinese Han Population. Oncotarget. Zuchthygiene. 2017;8(29):48313-20.PMID:28427149 2013;48(3):520-4.PMID:23131145 Zhu B, Dong Y, Xu Z, Gompf HS, Ward SA, Xue Z, et al. Tzanavari T, Giannogonas P, Karalis KP. TNF-alpha Sleep disturbance induces neuroinflammation and obesity. Current directions in autoimmunity. and impairment of learning and memory. 2010;11:145-56.PMID:20173393 Neurobiology of disease. Underwood EL, Thompson LT. A High-Fat Diet Causes 2012;48(3):348-55.PMID:22776332

REVISTAARGENTINA 2020, Vol. XXIX, N°4,969-980 DE CLÍNICA PSICOLÓGICA