Effects of saturated versus unsaturated fatty acids on metabolism, gliosis, and hypothalamic leptin sensitivity in male mice.

BACKGROUND: Development of obesity and its comorbidities is not only the result of excess energy intake, but also of dietary composition. Understanding how hypothalamic metabolic circuits interpret nutritional signals is fundamental to advance towards effective dietary interventions. OBJECTIVE: We aimed to determine the metabolic response to diets enriched in specific fatty acids. METHODS: Male mice received a diet enriched in unsaturated fatty acids (UOLF) or saturated fatty acids (SOLF) for 8 weeks. RESULTS: UOLF and SOLF mice gained more weight and adiposity, but with no difference between these two groups. Circulating leptin levels increased on both fatty acid-enriched diet, but were higher in UOLF mice, as were leptin mRNA levels in visceral adipose tissue. In contrast, serum non-esterified fatty acid levels only rose in SOLF mice. Hypothalamic mRNA levels of NPY decreased and of POMC increased in both UOLF and SOLF mice, but only SOLF mice showed signs of hypothalamic astrogliosis and affectation of central fatty acid metabolism. Exogenous leptin activated STAT3 in the hypothalamus of all groups, but the activation of AKT and mTOR and the decrease in AMPK activation in observed in controls and UOLF mice was not found in SOLF mice. CONCLUSIONS: Diets rich in fatty acids increase body weight and adiposity even if energy intake is not increased, while increased intake of saturated and unsaturated fatty acids differentially modify metabolic parameters that could underlie more long-term comorbidities. Thus, more understanding of how specific nutrients affect metabolism, weight gain, and obesity associated complications is necessary.

Regional specific effect of saturated vs unsaturated fat on leptin receptor signalling in mice brain areas regulating feeding.

Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake.

Long-Term Outcomes of Biological Therapy in Crohn's Disease Complicated With Internal Fistulizing Disease: BIOSCOPE Study From GETECCU.

INTRODUCTION: The prevalence of penetrating complications in Crohn's disease (CD) increases progressively over time, but evidence on the medical treatment in this setting is limited. The aim of this study was to evaluate the effectiveness of biologic agents in CD complicated with internal fistulizing disease. METHODS: Adult patients with CD-related fistulae who received at least 1 biologic agent for this condition from the prospectively maintained ENEIDA registry were included. Exclusion criteria involved those receiving biologics for perianal disease, enterocutaneous, rectovaginal, anastomotic, or peristomal fistulae. The primary end point was fistula-related surgery. Predictive factors associated with surgery and fistula closure were evaluated by multivariate logistic regression and survival analyses. RESULTS: A total of 760 patients from 53 hospitals (673 receiving anti-tumor necrosis factors, 69 ustekinumab, and 18 vedolizumab) were included. After a median follow-up of 56 months (interquartile range, 26-102 months), 240 patients required surgery, with surgery rates of 32%, 41%, and 24% among those under anti-tumor necrosis factor, vedolizumab, or ustekinumab, respectively. Fistula closure was observed in 24% of patients. Older patients, ileocolonic disease, entero-urinary fistulae, or an intestinal stricture distal to the origin of the fistula were associated with a higher risk of surgery, whereas nonsmokers and combination therapy with an immunomodulator reduced this risk. DISCUSSION: Biologic therapy is beneficial in approximately three-quarters of patients with fistulizing CD, achieving fistula closure in 24%. However, around one-third still undergo surgery due to refractory disease. Some patient- and lesion-related factors can identify patients who will obtain more benefit from these drugs.

Circadian rhythm drives the responsiveness of leptin-mediated hypothalamic pathway of cholecystokinin-8.

Cholecystokinin (CCK) and leptin act coordinately in the brain to regulate food intake and energy balance. Recently we have reported that CCK enhances the permeability of brain barriers to leptin and we have proposed that CCK enhances energy expenditure in rats by activating in the hypothalamus the janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, which is coupled to leptin receptors. Because plasma leptin concentration follows a circadian rhythm (plasma leptin concentration rise maximal values during the night, after rats start eating), we have hypothesized that the interaction between leptin and CCK should be more intense in animals receiving CCK during the night, i.e., during periods of positive energy balance. In order to further characterize the physiological relevance of the interplay between leptin and CCK we have compared the effect of diurnal vs. nocturnal administration of the C-terminal octapeptide of CCK (CCK-8) on (i) body weight and food intake, and (ii) STAT3 activation, by analyzing phosphorylated STAT3 (pSTAT3) immunostaining within the arcuate nucleus of the hypothalamus. Our results show that CCK decreases body weight and food intake only after p.m. administration. Accordingly pSTAT3 immunostaining within the hypothalamus was more intense in p.m. than in a.m.-treated animals. These data suggest that the effect of CCK on leptin pathways follows a circadian rhythm linked to the energy balance status and gives further support to the interaction between leptin and CCK.

Leptin-mediated hypothalamic pathway of cholecystokinin (CCK-8) to regulate body weight in free-feeding rats.

Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control.

Effect of peripheral cholecystokinin receptor agonists on c-Fos expression in brain sites mediating food consumption in rats.

Peripheral cholecystokinin (CCK) elicits satiety by acting on hypothalamic nuclei. The anoretic effect of CCK is mediated by the vagus nerve and involves brainstem areas receiving vagal inputs, such as the nucleus tractus solitarius (NTS) and the area postrema (AP). This work aims to analyze, by measuring c-Fos expression, the effect of selective CCK receptor agonists on brain areas involved in food-intake/satiety process. We observed that SR-146,131, a CCK(1)R agonist, increased c-Fos expression in NTS and AP as well as in some hypothalamic nuclei. CCK-4, a CCK(2)R agonist which does not cross the blood-brain barrier (BBB), only was effective in the hypothalamus. Our data show that the activation of the brainstem is not a requisite to obtain a hypothalamic effect of peripheral CCK and suggest that CCK-4 may indirectly stimulate hypothalamic areas endowed with BBB, without previous activation of neither NTS nor AP.