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Diabetes has been associated with an increased risk of cognitive decline and dementia. However, the mechanisms underlying this association remain unclear and no effective therapeutic interventions exist. Accumulating evidence demonstrates that mitochondrial defects are a key feature of diabetes contributing to neurodegenerative events. It has also been demonstrated that the putative tumor suppressor WW domain-containing oxidoreductase 1 (WWOX) can interact with mitochondria in several pathological conditions. However, its role in diabetes-associated neurodegeneration remains unknown. So, this study aimed to evaluate the role of WWOX activation in high glucose-induced neuronal damage and death. Our experiments were mainly performed in differentiated SH-SY5Y neuroblastoma cells exposed to high glucose and treated (or not) with Zfra1-31, the specific inhibitor of WWOX. Several parameters were analyzed namely cell viability, WWOX activation (tyrosine 33 residue phosphorylation), mitochondrial function, reactive oxygen species (ROS) production, biogenesis, and dynamics, autophagy and oxidative stress/damage. The levels of the neurotoxic proteins amyloid β (Aβ) and phosphorylated Tau (pTau) and of synaptic integrity markers were also evaluated. We observed that high glucose increased the levels of activated WWOX. Interestingly, brain cortical and hippocampal homogenates from young (6-month old) diabetic GK rats showed increased levels of activated WWOX compared to older GK rats (12-month old) suggesting that WWOX plays an early role in the diabetic brain. In neuronal cells, high glucose impaired mitochondrial respiration, dynamics and biogenesis, increased mitochondrial ROS production and decreased mitochondrial membrane potential and ATP production. More, high glucose augmented oxidative stress/damage and the levels of Aβ and pTau proteins and affected autophagy, contributing to the loss of synaptic integrity and cell death. Of note, the activation of WWOX preceded mitochondrial dysfunction and cell death. Importantly, the inhibition of WWOX with Zfra1-31 reversed, totally or partially, the alterations promoted by high glucose. Altogether our observations demonstrate that under high glucose conditions WWOX activation contributes to mitochondrial anomalies and neuronal damage and death, which suggests that WWOX is a potential therapeutic target for early interventions. Our findings also support the efficacy of Zfra1-31 in treating hyperglycemia/diabetes-associated neurodegeneration., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

It is widely accepted that high calorie diets and a sedentary lifestyle sturdily influence the incidence and outcome of type 2 diabetes and obesity, which can occur simultaneously, a situation called diabesity. Tightly linked with metabolic and energy regulation, a close association between diabetes and Alzheimer's disease (AD) has been proposed. Among the common pathogenic mechanisms that underpin both conditions, insulin resistance, brain glucose hypometabolism, and metabolic dyshomeostasis appear to have a pivotal role. This century is an unprecedented diabetogenic period in human history, so therapeutic strategies and/or approaches to control and/or revert this evolving epidemic is of utmost importance. This chapter will make a brief contextualization about the impact that diabetes and obesity can exert in brain structure and function alongside with a brief survey about the role of insulin in normal brain function, exploring its roles in cognition and brain glucose metabolism. Later, attention will be given to the intricate relation of diabesity, insulin resistance, and AD. Finally, both pharmacological and lifestyle interventions will also be reviewed as strategies aimed at fighting diabesity and/or AD-related metabolic effects.

Energy homeostasis is regulated by homeostatic and nonhomeostatic reward circuits which are closely integrated and interrelated. Before, during, and after meals, peripheral nutritional signals, through hormonal and neuronal pathways, are conveyed to selective brain areas, namely the hypothalamic nuclei and the brainstem, the main brain areas for energy balance regulation. These orexigenic and anorexigenic centers are held responsible for the integration of those signals and for an adequate output to peripheral organs involved in metabolism and energy homeostasis.Feeding includes also a hedonic behavior defined as food intake for pleasure independently of energy requirement. This nonhomeostatic regulation of energy balance is based on food reward properties, unrelated to nutritional demands, and involves areas like mesolimbic reward system, such as the ventral tegmental area and the nucleus accumbens, and also opioid, endocannabinoid, and dopamine systems.Herein, focus will be put on the brain circuits of homeostatic and nonhomeostatic regulation of food intake and energy expenditure.

Food intake and energy expenditure are closely regulated by several mechanisms which involve peripheral organs and nervous system, in order to maintain energy homeostasis.Short-term and long-term signals express the size and composition of ingested nutrients and the amount of body fat, respectively. Ingested nutrients trigger mechanical forces and gastrointestinal peptide secretion which provide signals to the brain through neuronal and endocrine pathways. Pancreatic hormones also play a role in energy balance exerting a short-acting control regulating the start, end, and composition of a meal. In addition, insulin and leptin derived from adipose tissue are involved in long-acting adiposity signals and regulate body weigh as well as the amount of energy stored as fat over time.This chapter focuses on the gastrointestinal-, pancreatic-, and adipose tissue-derived signals which are integrated in selective orexigenic and anorexigenic brain areas that, in turn, regulate food intake, energy expenditure, and peripheral metabolism.

Adipose tissue is an endocrine organ which is responsible for postprandial uptake of glucose and fatty acids, consequently producing a broad range of adipokines controlling several physiological functions like appetite, insulin sensitivity and secretion, immunity, coagulation, and vascular tone, among others. Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. Recent data suggest two main factors for adipose tissue dysfunction: accumulation of nonesterified fatty acids and their secondary products and hypoxia. Both of these factors are thought to be on the basis of low-grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. In turn, inflammation is involved in the inhibition of substrate uptake, alteration of the secretory profile, stimulation of angiogenesis, and recruitment of further inflammatory cells, which creates an inflammatory feedback in the tissue and is responsible for long-term establishment of insulin resistance.

Alzheimer's disease is the leading cause of dementia and the most prevalent neurodegenerative disease. It is an aging-related multi-factorial disorder and growing evidence support the contribution of metabolic factors to what was formerly thought to be a centrally mediated process. Obesity has already been recognized as an important player in the pathogenesis of this type of dementia, independently of insulin resistance or other vascular risk factors. Although the exact underlying mechanisms are still unknown, adipocyte dysfunction and concomitant alteration in adipocyte-derived protein secretion seem to be involved, since these adipocytokines can cross the blood-brain barrier and influence cognitive-related structures. Very few studies have assessed the role of adipocytokines dysfunction on cognitive impaired patients and yielded contradictory results. Interestingly, extensive research on the central effects of leptin in Alzheimer's disease-transgenic mice has demonstrated its capacity to enhance synaptic plasticity and strength, as well as to prevent beta-amyloid deposition and tau phosphorylation. In addition, adiponectin, the most abundant adipocytokine whose levels are inversely correlated to adiposity, has shown to be neuroprotective to hippocampal cells. Many other adipose-derived cytokines have mainly pro-inflammatory properties, being able to trigger and/or enhance central inflammatory cascades and also to influence the secretion of other adipocytokines involved in cognition. This paper pretends to review the existing evidence on the contribution of adipocytokines dysfunction to the increased risk of dementia associated with mid-life obesity, unraveling its insulin-independent effects on cognition.

Mitochondria have a crucial role in the supply of energy to the brain. Mitochondrial alterations can lead to detrimental consequences on the function of brain cells and are thought to have a pivotal role in the pathogenesis of several neurologic disorders. This study was aimed to evaluate mitochondrial function, fusion-fission and biogenesis and autophagy in brain cortex of 6-month-old Goto-Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes (T2D). No statistically significant alterations were observed in mitochondrial respiratory chain and oxidative phosphorylation system. A significant decrease in the protein levels of OPA1, a protein that facilitates mitochondrial fusion, was observed in brain cortex of GK rats. Furthermore, a significant decrease in the protein levels of LC3-II and a significant increase in protein levels of mTOR phosphorylated at serine residue 2448 were observed in GK rats suggesting a suppression of autophagy in diabetic brain cortex. No significant alterations were observed in the parameters related to mitochondrial biogenesis. Altogether, these results demonstrate that during the early stages of T2D, brain mitochondrial function is maintained in part due to a delicate balance between mitochondrial fusion-fission and biogenesis and autophagy. However, future studies are warranted to evaluate the role of mitochondrial quality control pathways in late stages of T2D.

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently received attention due to the new and contrasting findings regarding its effects on mitochondrial function. In the present study, we evaluated the effect of metformin in isolated rat liver mitochondria status. We observed that metformin concentrations > or =8 mM induce an impairment of the respiratory chain characterized by a decrease in RCR and state 3 respiration. However, only metformin concentrations > or =10 mM affect the oxidative phosphorylation system by decreasing the mitochondrial transmembrane potential and increasing the repolarization lag phase. Moreover, our results show that metformin does not prevent H(2)O(2) production, neither protects against lipid peroxidation induced by the pro-oxidant pair ADP/Fe(2+). In addition, we observed that metformin exacerbates Ca(2+)-induced permeability transition pore opening by decreasing the capacity of mitochondria to accumulate Ca(2+ )and increasing the oxidation of thiol groups. Taken together, our results show that metformin can promote liver mitochondria injury predisposing to cell death.

Increasing evidence shows that the overproduction of reactive oxygen species, induced by diabetic hyperglycemia, contributes to the development of several cardiopathologies. The susceptibility of diabetic hearts to oxidative stress, induced in vitro by ADP-Fe2+ in mitochondria, was studied in 12-month-old Goto-Kakizaki rats, a model of non-insulin dependent diabetes mellitus, and normal (non-diabetic) Wistar rats. In terms of lipid peroxidation the oxidative damage was evaluated on heart mitochondria by measuring both the O2 consumption and the concentrations of thiobarbituric acid reactive substances. Diabetic rats display a more intense formation of thiobarbituric acid reactive substances and a higher O2 consumption than non-diabetic rats. The oxidative damage, assessed by electron microscopy, was followed by an extensive effect on the volume of diabetic heart mitochondria, as compared with control heart mitochondria. An increase in the susceptibility of diabetic heart mitochondria to oxidative stress can be explained by reduced levels of endogenous antioxidants, so we proceeded in determining alpha-tocopherol, GSH and coenzyme Q content. Although no difference of alpha-tocopherol levels was found in diabetic rats as compared with control rat mitochondria, a significant reduction in GSH (21.5% reduction in diabetic rats) and coenzyme Q levels of diabetic rats was observed. The data suggest that a significant decrease of coenzyme Q9, a potent antioxidant involved in the elimination of mitochondria-generated reactive oxygen species, may be responsible for an increased susceptibility of diabetic heart mitochondria to oxidative damage.