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Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. Accordingly, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist) or a green fluorescence protein (GFP) (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin, whereas males rapidly lost physiological effects and developed leptin resistance as confirmed by lower acute leptin-mediated phosphorylation of signal transducer and activator of transcription 3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist- females gained lean body mass. Consequently, the lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, the present study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether such physiological responses are mediated by female or male sex hormones. [ABSTRACT FROM AUTHOR]

Diet-induced obesity is associated with hypothalamic inflammation and this phenomenon has been proposed to explain leptin resistance. In the present study, we used a short-term high-fat diet ( HFD) paradigm for 10 days and analysed the cellular and physiological responses to leptin administration in C57 BL6 mice. In parallel, we performed glial fibrillary acidic protein immunostaining to measure the presence of astrocytes in the arcuate nucleus of the hypothalamus ( ARH) after 10 days and 20 weeks of HFD. Interestingly, the results obtained demonstrate that the presence of star-like astrocytes is significantly increased after 10 days of HFD, although this is not associated with the absence of cellular and physiological response to leptin administration in mice. Taken together, the results of the present study suggest that star-like astrocytes rapidly increase in numbers in the ARH in response to HFD, although this phenomenon cannot explain the development of leptin resistance by itself. [ABSTRACT FROM AUTHOR]

The phosphodiesterase-3 B ( PDE3B)- cAMP pathway plays an important role in transducing the action of leptin in the hypothalamus. Obesity is usually associated with hyperleptinaemia and resistance to anorectic and body weight-reducing effects of leptin. To determine whether the hypothalamic PDE3B- cAMP pathway of leptin signalling is impaired during the development of diet-induced obesity ( DIO), we fed male FVB/ N mice a high-fat diet ( HFD: 58% kcal as fat) or low-fat diet ( LFD: 6% kcal as fat) for 4 weeks. HFD fed mice developed DIO in association with hyperphagia, hyperleptinaemia and hyperinsulinaemia. Leptin (i.p.) significantly increased hypothalamic PDE3 B activity and phosphorylated (p)- Akt levels in LFD-fed but not in HFD-fed mice. However, basal p- Akt levels in hypothalamus were increased in DIO mice. Additionally, amongst six-microdissected brain nuclei examined, leptin selectively decreased cAMP levels in the arcuate nucleus ( ARC) of LFD-fed mice but failed to do so in HFD-fed mice. We next tested whether both the PBE3 B and Akt pathways of leptin signalling remained impaired in DIO mice on the HFD for 12 weeks (long-term). DIO mice were hyperinsulinaemic and hyperleptinaemic in association with impaired glucose and insulin tolerance. Although, in LFD-fed mice, leptin significantly increased PDE3 B activity and p- Akt levels in the hypothalamus, it failed to do so in HFD-fed mice. Also, basal p- Akt levels in the hypothalamus were increased in DIO mice and leptin had no further effect. Similarly, immunocytochemistry showed that leptin increased the number of p- Akt-positive cells in the ARC of LFD-fed but not in HFD-fed mice, and there was an increased basal number of p- Akt positive cells in the ARC of DIO mice. These results suggest that the PDE3 B- cAMP- and Akt-pathways of leptin signalling in the hypothalamus are impaired during the development of DIO. Thus, a defect in the regulation by leptin of the hypothalamic PDE3 B- cAMP pathway and Akt signalling may be one of the mechanisms of central leptin resistance and the development of DIO. [ABSTRACT FROM AUTHOR]

Hypothalamic leptin resistance during pregnancy is an important adaptation that facilitates the state of positive energy balance required for fat deposition in preparation for lactation. Within the arcuate nucleus, pro-opiomelanocortin (POMC) neurones and neuropeptide Y (NPY)/agouti-related gene protein (AgRP) neurones are first-order leptin responsive neurones involved in the regulation of energy balance. The present study aimed to investigate whether the regulation of these neuropeptides is disrupted during pregnancy in association with the development of leptin resistance. As measured by quantitative in situ hybridisation, POMC and AgRP mRNA levels were not significantly different during pregnancy, whereas NPY mRNA levels increased such that, by day 21 of pregnancy, levels were significantly higher than in nonpregnant, animals. These data suggest that these neurones were not responding normally to the elevated leptin found during pregnancy. To further characterise the melanocortin system during pregnancy, double-label immunohistochemistry was used to quantify leptin-induced phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in POMC neurones, using α-melanocyte-stimulating hormone (MSH) as a marker. The percentage of α-MSH neurones containing leptin-induced pSTAT3 did not significantly differ from nonpregnant animals, indicating that there was no change in the number of POMC neurones that respond to leptin during pregnancy. Treatment with α-MSH significantly reduced food intake in nonpregnant rats, but not in pregnant rats, indicating resistance to the satiety actions of α-MSH during pregnancy. The data suggest that multiple mechanisms contribute to leptin resistance during pregnancy. As well as a loss of responses in first-order leptin-responsive neurones in the arcuate nucleus, there is also a downstream disruption in the melanocortin system. [ABSTRACT FROM AUTHOR]

Leptin acts within the hypothalamus to diminish food intake. In Brandt’s voles ( Lasiopodomys brandtii), both circulating leptin levels and food intake are elevated during pregnancy, suggesting an ineffectiveness of leptin to reduce food intake. Diminished hypothalamic leptin receptors and impaired leptin signal transduction are characteristic of central leptin resistance. The present study aimed to determine whether these characteristic modulations of leptin sensitivity occurred in pregnant Brandt’s voles. The mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling 3 (SOCS3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 10 and day 18 of pregnancy. Compared to controls, there was no significant change in hypothalamic Ob-Rb mRNA during the pregnancy. SOCS3 mRNA was increased significantly by 68% on day 10% and 93% on day 18 of pregnancy compared to controls. Despite elevated leptin levels, POMC mRNA was decreased significantly by 60% on day 18 of pregnancy, whereas no differences were found in the mRNA expression of NPY, AgRP and CART in pregnant voles compared to controls. The elevation of SOCS3 mRNA together with disrupted leptin regulation of neuropeptides in the hypothalamus suggests that leptin resistance may develop in pregnant Brandt’s voles. [ABSTRACT FROM AUTHOR]

The adipose-derived hormone leptin primarily acts in the hypothalamus to decrease appetite and increase energy expenditure, thereby maintaining body fat levels around a set point. Pregnancy is a physiological state where this feedback mechanism is not beneficial. Successful reproductive efforts are highly demanding on the resources of the mother; thus, it is imperative that the maternal body can increase energy stores without restraint. Food intake, fat mass and serum leptin concentrations increase during pregnancy in the rat, suggesting that the feedback loop between adipose tissue and appetite is disrupted and a state of leptin resistance exists. In support of this, there is an attenuation of the satiety response to exogenous leptin administration in pregnant rats. This state of leptin resistance is associated with impaired activation of the leptin-induced Janus activating kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway in the ventromedial nucleus of the hypothalamus (VMH) and arcuate nucleus, and reduced expression of leptin receptor mRNA in the VMH. Furthermore, pregnant rats do not show a satiety response to exogenous alpha-melanocyte stimulating hormone. This model offers the possibility of examining how hypothalamic leptin signalling can be modified in response to changes in physiological conditions. [ABSTRACT FROM AUTHOR]

We have previously shown that cold-acclimated (8 °C) male field voles ( Microtus agrestis) transferred from short day (SD, 8 h light) to long day (LD, 16 h light) photoperiod exhibit an increase in body mass lasting 4 weeks, after which they stabilise at a new plateau approximately 7.5 g (24.8%) higher than animals maintained in SD. By infusing voles with exogenous leptin, we have also demonstrated that SD voles respond to the hormone by reducing body mass and food intake, whereas LD animals increasing body mass are resistant to leptin treatment. In the present study, we investigated whether seasonal changes in body mass could be linked to modulation of the leptin signal by suppressor of cytokine signalling-3 (SOCS3). We used in situ hybridisation to examine hypothalamic arcuate nucleus (ARC) expression of SOCS3, neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) genes in 90 voles exposed to either SD or LD for up to 11 weeks. LD voles increasing body mass had significantly higher levels of SOCS3 mRNA than SD or LD voles with a stable body mass. There were no associated changes in expression of NPY, AgRP, POMC and CART genes. These results suggest that voles that regulate body mass at either the lower (SD) or upper (LD) plateau remain sensitive to leptin action, whereas SOCS3-mediated leptin resistance is a short-term mechanism that enables animals to move between the stable body mass plateaus. Our data provide evidence that expression of SOCS3 in the ARC is involved in the modulation of the strength of the leptin signal to facilitate seasonal cycles in body mass and adiposity. [ABSTRACT FROM AUTHOR]

Abstract Leptin regulates food intake and body weight by acting primarily in the hypothalamus. In humans and rodents, obesity is associated with hyperleptinaemia, suggesting a possible state of leptin resistance. Thus, to begin to examine the mechanisms of leptin resistance, we developed a rat model in which chronic central leptin infusion results in the development of resistance to leptin's satiety action. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or phosphate-buffered saline via Alzet pumps for 28 days, followed by artificial cerebrospinal fluid infusion for 3 weeks. After the initial decrease in food intake, rats developed resistance to the satiety action of leptin, and withdrawal of the chronic leptin infusion resulted in hyperphagia. During leptin infusion, body weight was gradually decreased to reach a nadir on day 12, and thereafter, body weight was sustained at a reduced level throughout the entire 28-day infusion, despite normalization in food intake. Body weight was mostly normalized by day 22 postleptin. Since neuropeptide Y (NPY) neurones are one of the targets of leptin signalling in the hypothalamus, we next examined whether the development of resistance to the satiety action of leptin was due to altered NPY gene expression. On day 3–4 of infusion, hypothalamic NPY mRNA levels, as determined by RNAse protection assay (RPA), were significantly decreased in leptin treated rats compared to controls. By contrast, on day 16 of infusion, NPY mRNA levels in the leptin treated group had returned to control levels. In situ hybridization study confirmed the results obtained with RPA and showed further that the effect of chronic leptin infusion on NPY mRNA levels was restricted to the rostral and middle parts of the arcuate nucleus. Overall, the finding that the action of continuous leptin exposure on NPY neurones was not sustained suggests that NPY neurones may be involved in the development of... [ABSTRACT FROM AUTHOR]