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Obesity is caused as the consequence of positive energy balance, which increases the amount of lipid in adipose tissue. The intake of excessive amounts of fatty acids promote lipotoxicity, consequently increases the risk for cardiovascular diseases, insulin resistance, dyslipidemia, diabetes, and obesity. The percentage of patients with peripheral neuropathy was more frequent in groups with the high Body Mass Index (BMI) ( ≥ 30 kg/m2) compared to the low BMI (<30 kg/m2) [1]. Free fatty acids accelerate mitochondrial fission and promote Reactive Oxygen Species (ROS) production [2]. ROSinduced oxidative stress promotes dysfunction in peripheral nerves [3]. Thus, it is assumed that lipotoxicity enhances the development of peripheral neuropathy.

Obviously, males and females experience many diseases and disorders differently. Sex hormones, such as estrogen, progesterone, and androgen, contribute to the sex differences in metabolism between males and females and are thought to be responsible for sex-specific differences [4,5]. Several studies have reported that the sex-specific adverse effects were observed in peripheral nerves [6-10].This review focuses on the sex difference in lipotoxicity in peripheral nerves.

Peripheral neuropathy, a result of damage to peripheral nerves, frequently causes numbness and pain, in the whole body, particularly extremities. The major categories of peripheral nerve injury (neuropathy) are generally neuronopathy, axonopathy, and myelinopathy [11]. Neuronopathy is induced by cell death such as apoptosis and/or autophagy in the cell body of neurons [12,13]. In axonopathy, axon degeneration will lead to secondary loss of the myelin sheath. Myelinopathy is caused by the destruction of the myelin sheath. Apoptosis is a programmed mechanism of cell death that is triggered in response to cellular stress. BCL2 family proteins, such as BAX and BCL2, are key regulators of apoptosis. BAXactivated Caspase-3 initiates DNA fragmentation, thereby leading to cell death. On the other hand, autophagy is a lysosomal degradation pathway. Autophagy can be either non-selective or selective. In selective autophagy, autophagy receptors bind to cargoes and result in degradation within lysosomes/vacuoles, depending on the core autophagy machinery. p62/SQSTM1 is a key autophagy receptor that can shuttle ubiquitinated cargo for autophagic degradation.

Fatty acids are chemically classified as saturated and unsaturated, and each of them has specific biological functions. Interestingly, saturated fatty acids induce apoptosis [14] and unsaturated fatty acids induce autophagy [15]. Recently, Ogawa et al. also reported that saturated fatty acid-induced apoptosis marker and unsaturated fatty acid increased the level of the autophagy-related gene in neural cells [16,17]. However, the mechanism by which fatty acids induce different molecular cell death (apoptosis and autophagy) dependent on saturation remains unclear. In animal studies, High-Fat Diets (HFD) rich in both saturated and unsaturated fatty acids are often used to induce obesity, and many studies have reported that the HFD induces apoptosis in hepatocytes and cardiomyoblasts [18]. Similarly, Ogawa et al. recently reported that the HFD induced the increase of apoptosis markers in the peripheral nerves.In neural cells, the treatment of fatty acids induced protein expression of BAX and the number of apoptotic cells [19]. By contrast, mice fed the HFD have reduced hepatic autophagy [20]. The HFD inhibits autophagy in cardiomyocytes. Therefore, the mixtures of saturated and unsaturated fatty acids probably induce apoptosis but not autophagy

Sex hormones, such as estrogen, progesterone, and androgen, contribute to the sex differences in metabolism between males and females and are responsible for sex-specific differences. The pathogenesis of neuropathy is enhanced in the sciatic nerves of male mice fed the HFD. Male mice are more vulnerable than the females to the impacts of the HFD on weight gain, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity. Male rats with diabetes have a higher frequency of neuropathy than female rats with diabetes [21]. Similarly, male mice develop a greater extent of diabetes-induced cognition deficits and peripheral neurovascular dysfunction than female mice [22]. In our recent study, HFD induced apoptosis in the sciatic nerves of males, but not females. Therefore, these indicate that there is a sex difference in peripheral neuropathy.

In ovariectomized females fed the HFD, the levels of the apoptosisrelated genes were increased compared to ovariectomized mice fed a normal diet. In contrast, the replacement of estrogen, a female hormone, in ovariectomized mice abolished the HFD-induced mRNA levels of two apoptosis-related genes.Thus, it is assumed that estrogen has prevented the cell damage of central and peripheral nerves.

Estrogen signaling is mediated by binding to estrogen receptor α (ERα) and/or ERβ, which are a member of the nuclear receptor family. The function of estrogen can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Estrogen prevents apoptosis via ERsmediated non-genomic actions in many cell types [23]. Both ERα and ERβ are expressed in the brain [24] and peripheral neurons [25]. ERs are necessary for the embryonic development of the brain.

Fatty acids induce oxidative stress and inflammation, consequently lead to cell death [26,27]. Estrogen mediates neuroprotection and antiinflammatory effects through ERα signaling on astrocytes and neurons [28]. Estrogen also attenuates ischemic oxidative damage via an ERα- mediated inhibition of NADPH oxidase activation [29]. In short, estrogen exerts anti-inflammatory and anti-oxidant properties. Cerebral ischemia is followed by a local inflammatory response that contributes to tissue damage. The harmful effects are caused due to excess nitric oxide (NO) production by the inducible isoform of NO synthase (iNOS). Another study has shown that the decrease of iNOS expression by estrogen is one of the factors mediating the resistance to cerebral ischemia in females [30]. In female rats, the HFD led to increased iNOS expression and decreased levels of estrogen and ERα protein in the HFD-fed group [31]. Estrogen and ERα-selective agonist, but not ERβ-selective agonist, prevented the oleic acidinduced cytotoxicity in Neuro-2a neural cells. Thus, these indicate that estrogen prevents the fatty acid-induced oxidative stress and inflammation via ERα in peripheral nerves.

Oleic acid, an unsaturated fatty acid, induced autophagy but had a minimal effect on apoptosis. In contrast, palmitic acid, a saturated fatty acid, was suppressed autophagy, and significantly induced apoptosis in hepatocytes. Neuroprotective effects of estrogen in the peripheral neuron are partly related to the suppression of excessive autophagy [32]. The knockdown of ERα induces autophagy and promotes ROS-induced cell death in breast cancer cells [33], therefore estrogen inhibits autophagy via ERα. Estrogen inhibited the oleic acid has induced cytotoxicity, and enhanced the stearic acid induced cytotoxicity at high concentrations. On the other hand, ERβ-selective agonist slightly enhanced the oleic acid-induced cytotoxicity and induced the increase of p62/Sqstm1 mRNA in Neuro-2a neural cells . ERα and ERβ are known to undertake different effects in various tissues [34,35]. A recent study has reported that ERβ promotes autophagy in neural cells [36]. Therefore, these suggest that estrogen plays probably the different roles between saturated fatty acids and unsaturated fatty acids, and ERβ may have the opposite effects of ERα in neural cells. Further studies are needed to understand the role of ER isoforms in neuron injury.

HFD-induced lipotoxicity enhances the development of peripheral neuropathy in males only. In females, estrogen attenuated HFD feeding damaged the sciatic nerves. In short, estrogen is assumed to be responsible for sex differences in the injury of sciatic nerves. In vitro studies indicate that estrogen plays probably the different roles between saturated fatty acids and unsaturated fatty acids. In neural cells, ERα prevents the saturated fatty acid-induced cytotoxicity by the inhibitory effects of oxidative stress and inflammation, and ERβ promotes cytotoxicity. ERα and ERβ are known to exert different effects in various tissues. Therefore, ERβ may have the opposite effects of ERα in neural cells. Further studies are needed to understand the role of ER isoforms in neuron injury.