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Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson’s and Alzheimer’s diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 μg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion.

Dietary restriction is a frequent strategy for weight loss, but adherence is difficult and returning to poor dietary habits can result in more weight gain than that previously lost. How weight loss due to unrestricted intake of a healthy diet affects the response to resumption of poor dietary habits is less studied. Moreover, whether this response differs between the sexes and if the insulin-like growth factor (IGF) system, sex dependent and involved in metabolic control, participates is unknown. Mice received rodent chow (6% Kcal from fat) or a high-fat diet (HFD, 62% Kcal from fat) for 4 months, chow for 3 months plus 1 month of HFD, or HFD for 2 months, chow for 1 month then HFD for 1 month. Males and females gained weight on HFD and lost weight when returned to chow at different rates (p < 0.001), but weight gain after resumption of HFD intake was not affected by previous weight loss in either sex. Glucose metabolism was more affected by HFD, as well as the re-exposure to HFD after weight loss, in males. This was associated with increases in hypothalamic mRNA levels of IGF2 (p < 0.01) and IGF binding protein (IGFBP) 2 (p < 0.05), factors involved in glucose metabolism, again only in males. Likewise, IGF2 increased IGFBP2 mRNA levels only in hypothalamic astrocytes from males (p < 0.05). In conclusion, the metabolic responses to dietary changes were less severe and more delayed in females and the IGF system might be involved in some of the sex specific observations.

Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons.

The propensity to develop neurodegenerative diseases is influenced by diverse factors including genetic make-up, sex, lifestyle, including dietary habits and being overweight, and age. Indeed, with aging there is an increased incidence of both obesity and neurodegenerative processes, both of which are associated with inflammatory processes, in a sex specific manner. Although aging-induced modifications in sex steroids and increased cell stress are involved, there is a complex interaction between these process that remains to be understood. Here we have analyzed the metabolic and inflammatory responses of middle-aged transgenic amyloid precursor protein (TgApp) mice of both sexes to a high fat diet (HFD) for 18 weeks. We found clear sex differences with females gaining significantly more weight and fat mass than males, in addition to a larger increase in circulating leptin levels and expression of inflammatory markers in visceral adipose tissue. However, glycemia and insulin levels increased in HFD fed mice of both sexes, with TgAPP mice being more affected than wild type (WT) mice. In the hypothalamus, amyloid β levels were increased by HFD intake exclusively in males and reaching statistical significance only in APP males. On a low fat diet (LFD), TgAPP males had significantly lower mRNA levels of the anorexigenic neuropeptide proopiomelanocortin (POMC) than WT males, with HFD intake decreasing the expression of the orexigenic neuropeptides Agouti related peptide (AgRP) and neuropeptide Y (NPY), especially in TgAPP mice. In contrast, in females there was no effect of genotype on these metabolic neuropeptides, with HFD increasing POMC mRNA levels but with no effect on AgRP or NPY mRNA levels. We found no effect of diet or genotype on the inflammatory markers analyzed in the hypothalamus. Likewise, no differences in glial acidic protein (GFAP) levels were found; however, there was an increase in the levels of the microglial marker Iba1 selectively in male TgAPP mice. Together these data indicate that there is a complex interaction between sex and the expression of APP on the hypothalamus and the metabolic response to high fat diet intake.

An excess of saturated fatty acids can be toxic for tissues, including the brain, and this has been associated with the progression of neurodegenerative diseases. Since palmitic acid (PA) is a free fatty acid that is abundant in the diet and circulation and can be harmful, we have investigated the effects of this fatty acid on lipotoxicity in hippocampal astrocytes and the mechanism involved. Moreover, as males and females have different susceptibilities to some neurodegenerative diseases, we accessed the responses of astrocytes from both sexes, as well as the possible involvement of estrogens in the protection against fatty acid toxicity. PA increased endoplasmic reticulum stress leading to cell death in astrocytes from both males and females. Estradiol (E2) increased the levels of protective factors, such as Hsp70 and the anti-inflammatory cytokine interleukin-10, in astrocytes from both sexes. In male astrocytes, E2 decreased pJNK, TNFα, and caspase-3 activation. In contrast, in female astrocytes E2 did not affect the activation of JNK or TNFα levels, but decreased apoptotic cell death. Hence, although E2 exerted protective effects against the detrimental effects of PA, the mechanisms involved appear to be different between male and female astrocytes. This sexually dimorphic difference in the protective mechanisms induced by E2 could be involved in the different susceptibilities of males and females to some neurodegenerative processes.

Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.

Insulin receptor substrate-2-deficient (IRS2−/−) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2−/− mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2−/− mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2−/− mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2−/− mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus.

Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations.