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.

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.

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.

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice.

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.

Short-Term Diet Induced Changes in the Central and Circulating IGF Systems Are Sex Specific.

Insulin-like growth factor (IGF) 1 exerts a wide range of functions in mammalians participating not only in the control of growth and metabolism, but also in other actions such as neuroprotection. Nutritional status modifies the IGF system, although little is known regarding how diet affects the newest members of this system including pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2, proteases that liberate IGF from the IGF-binding proteins (IGFBPs), and stanniocalcins (STCs) that inhibit PAPP-A and PAPP-A2 activity. Here we explored if a 1-week dietary change to either a high-fat diet (HFD) or a low-fat diet (LFD) modifies the central and peripheral IGF systems in both male and female Wistar rats. The circulating IGF system showed sex differences in most of its members at baseline. Males had higher levels of both free (p < 0.001) and total IGF1 (p < 0.001), as well as IGFBP3 (p < 0.001), IGFBP5 (p < 0.001), and insulin (p < 0.01). In contrast, females had higher serum levels of PAPP-A2 (p < 0.05) and IGFBP2 (p < 0.001). The responses to a short-term dietary change were both diet and sex specific. Circulating levels of IGF2 increased in response to LFD intake in females (p < 0.001) and decreased in response to HFD intake in males (p < 0.001). In females, LFD intake also decreased circulating IGFBP2 levels (p < 0.001). In the hypothalamus LFD intake increased IGF2 (p < 0.01) and IGFBP2 mRNA (p < 0.001) levels, as well as the expression of NPY (p < 0.001) and AgRP (p < 0.01), but only in males. In conclusion, short-term LFD intake induced more changes in the peripheral and central IGF system than did short-term HFD intake. Moreover, these changes were sex-specific, with IGF2 and IGFBP2 being more highly affected than the other members of the IGF system. One of the main differences between the commercial LFD employed and the HFD or normal rodent chow is that the LFD has a significantly higher sucrose content, suggesting that this nutrient could be involved in the observed responses.