Palmitic acid modulation of the insulin-like growth factor system in hypothalamic astrocytes and neurons.

INTRODUCTION: Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. METHODS: Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. RESULTS: In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2 and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effect of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. CONCLUSIONS: The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.

The differential effects of palmitic acid and oleic acid on the metabolic response of hypothalamic astrocytes from male and female mice.

Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid ß-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.

Synergism Between Hypothalamic Astrocytes and Neurons in Metabolic Control.

Astrocytes are no longer considered as passive support cells. In the hypothalamus, these glial cells actively participate in the control of appetite, energy expenditure, and the processes leading to obesity and its secondary complications. Here we briefly review studies supporting this conclusion and the advances made in understanding the underlying mechanisms.

The metabolic effects of resumption of a high fat diet after weight loss are sex dependent in mice.

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.

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies.

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.

Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice.

Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.