MR blockade protects against diet induced obesity, adipocyte dysfunction and cardiac inflammation in mice, through browning of the adipose organ and modulation of autophagy

Obesity is a key factor in the development of insulin resistance (IR), cardiovascular disease, hypertension, type 2 diabetes etc. Given the near epidemic incidence of obesity in western society there is a clear need for effective treatment options. Mineralocorticoid receptor (MR) blockade has shown significant promise in transgenic mouse models of obesity in limiting IR and adipocyte dysfunction, a disease that is independent of classical MR actions (renal). Female 10-weekold C57bl6 mice were fed with normal chow or a high fat (HF) diet for 12 weeks. Mice fed HF diet were concomitantly treated for 12 weeks with drospirenone (DRSP, 6 mg/kg/day), a potent MR antagonist with antiadipogenic activity, or spironolactone (SPIRO, 20 mg/kg/day). Mice fed HF diet showed a significant increase in total body weight, fat mass, mean adipocyte size, expression of white adipose tissue (WAT) marker genes and showed impaired glucose tolerance after intraperitoneal plasma glucose tolerance test. DRSP and SPIRO prevented weight gain and white fat mass expansion induced by HF diet in parametrial, perivescical, and inguinal depots without affecting interscapular fat pad weight. Magnetic Resonance Imaging (MRI) confirmed that MR antagonists blocked the HF dietdriven expansion of abdomino-pelvic (parametrial and perivescical) fat volume. High levels of MR mRNA were detected in all depots of adipose tissue. HF fed mice showed no increase in heart or kidney weight and tissue fibrosis. Cardiac macrophage recruitment and osteopontin staining was increased in hearts of HF fed mice and reversed by both MR antagonists. Moreover, both DRSP and SPIRO prevented the impaired glucose tolerance in mice fed HF diet, and countered HF diet-induced up-regulation of WAT markers transcripts and adipocyte hypertrophy. Importantly, MR antagonists increased uncoupling protein 1 (UCP-1) positive brown-like adipocyte content in WAT, and improved metabolic activity of adipose tissue, as indicated by PET/CT imaging. In keeping with this, MR antagonism significantly increased expression of brown-like adipocyte marker genes such PRDM16, CIDEA, beta-3 adrenergic receptor (ADRB3) and UCP-1 in all WAT depots analysed. In exploring the mechanism, we demonstrated that MR antagonism induced brown adipose tissue (BAT) markers, and reduced the autophagic rate, a key remodelling process in adipocyte differentiation, in WAT depots in vivo as well as in primary cultured adipocytes. We conclude that adipocyte MR regulates BAT-like remodeling of WAT through modulation of autophagy. MR blockade therefore has promise as a novel therapeutic option for the prevention of metabolic dysfunctions and the cardiac consequences of obesity. doi:10.1016/j.ijcme.2015.05.012 Transcriptional control of ICAM-1 in human coronary artery endothelial cells by Mineralocorticoid Receptor (MR): Implications for the protective effects of MR antagonists in cardiovascular diseases V. Marzolla, A. Armani, A. Fabbri, I.Z. Jaffe, M. Caprio Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy Department of Medicina dei Sistemi, Endocrinology Unit, S. Eugenio & CTO A. Alesini Hospitals, University Tor Vergata, Rome, Italy Molecular Cardiology Research Institute, Tufts Medical Center, Boston

Calving difficulty influences rumination time and inflammatory profile in Holstein dairy cows

Difficult calving may adversely affect dairy cow health and performance. Maternal:fetal disproportion is a major cause of dystocia. Therefore, the main objective of this study was to assess the effects of dam:calf body weight ratio (D:C) on calving difficulty, rumination time, lying time, and inflammatory profile in 25 Holstein dairy cows. Using automatic monitoring systems, we monitored behavior and production in 9 primiparous and 16 pluriparous cows between dry-off and 30 d in milk. During the same period, we collected blood samples to monitor metabolism and inflammatory profile of these cows. Calvings were video recorded to assess calving difficulty and observe the duration of the expulsive stage. After parturition, the cows were separated into 3 classes according to their D:C: easy (E; D:C >17), medium (M; 14 < D:C <17), and difficult (D; D:C <14). The cows in class D showed relatively longer labor durations (108 min vs. 54 and 51 min for classes D, M, and E, respectively) and higher calving assistance rates (50% vs. 0 and 11% of calvings for classes D, M, and E, respectively) than those in the other 2 classes. Compared with the cows in classes M and E, those in class D exhibited shorter rumination times on the day of calving (176 min/d vs. 288 and 354 min/d for classes D, M, and E, respectively) and during the first week of lactation (312 min/d vs. 339 and 434 min/d for classes D, M, and E, respectively) and maintained lower rumination values until 30 DIM (399 min/d vs. 451 and 499 min/d for classes D, M, and E, respectively). Primiparous class D cows had shorter resting times during the first week after calving compared with those in class M (8 vs. 11 h/d for classes D and M, respectively). Interclass differences were found in terms of the levels of inflammation markers such as acute-phase proteins (ceruloplasmin, albumin, retinol, and paraoxonase). Moreover, cows in class D had lower plasma levels of fructosamine and creatinine after calving. Low D:C reduced postcalving rumination time and increased inflammation grade, suggesting a lower welfare of these animals at the onset of lactation. The D:C might serve as a useful index for the identification of cows at relatively higher risk of metabolic and inflammatory disease, thus helping farmers and veterinarians improve the welfare and health of these cows

The use of monensin for ketosis prevention in dairy cows during the transition period: A systematic review

Since the approval by the European Medicines Agency in 2013 of a monensin controlled-release capsule (CRC) for the prevention of ketosis in dairy cows, there has been widespread use across Europe. In recent decades, several papers have investigated the effects of monensin used as a CRC or as a feed additive to improve cattle energy metabolism and improve feed efficiency. Since the CRC is the only form of monensin permitted in Europe in dairy cows, the objective of this review was to report and summarize observations from the literature on the effects of this treatment in transition cows. The peer-reviewed literature published from 1997 was scanned, and papers written in English were evaluated for eligibility. Only papers evaluating the use of monensin in dairy cows for the prevention of ketosis during the transition period were reviewed. In total, 42 papers met the required criteria and were included in this review. The major findings focused on cow metabolism and health, rumen fermentation and milk production and quality. Overall, the review of the existing literature confirmed that monensin delivered as a CRC during the transition period has effects of different magnitude compared to other forms, doses or durations of administration. Studies agree on the antiketotic effects of this treatment, showing evidence of an increased propionate production in the rumen, reduced blood β-hydroxybutyrate, and improved liver function in treated cows, mainly resulting in reduced incidence of peripartum disease. On the contrary, the effects of CRC on ammonia production and rumen microflora are less robust than those reported for other forms. Of importance for the European market is the well-documented absence of any negative impact on milk and cheese production and composition using the CRC treatment

Overstocking dairy cows during the dry period affects dehydroepiandrosterone and cortisol secretion

Stressful situations trigger several changes such as the secretion of cortisol and dehydroepiandrosterone (DHEA) from the adrenal cortex, in response to ACTH. The aim of this study was to verify whether overstocking during the dry period (from 21 \ub1 3 d to the expected calving until calving) affects DHEA and cortisol secretion and behavior in Holstein Friesian cows. Twenty-eight cows were randomly divided into 2 groups (14 animals each), balanced for the number of lactations, body condition score, and expected date of calving. Cows in the far-off phase of the dry period (from 60 to 21 d before the expected calving date) were housed together in a bedded pack. Then, animals from 21 \ub1 3 d before the expected calving until calving were housed in pens with the same size but under different crowding conditions due to the introduction of heifers (interference animals) into the pen. The control condition (CTR) had 2 animals per pen with 12.0 m2 each, whereas the overstocked condition (OS) had 3 interference animals in the same pen with 4.8 m2 for each animal. On d 1230 \ub1 3, 1221 \ub1 3, 1215 \ub1 3, 1210 \ub1 3, and 125 \ub1 3 before and 10, 20, and 30 after calving, blood samples were collected from each cow for the determination of plasma DHEA and cortisol concentrations by RIA. Rumination time (min/d), activity (steps/h), lying time (min/d), and lying bouts (bouts/d) were individually recorded daily. In both groups, DHEA increased before calving and the concentration declined rapidly after parturition. Overstocking significantly increased DHEA concentration compared with the CTR group at d 1210 (1.79 \ub1 0.09 vs. 1.24 \ub1 0.14 pmol/mL), whereas an increase of cortisol was observed at d 1215 (3.64 \ub1 0.52 vs. 1.64 \ub1 0.46 ng/mL). The OS group showed significantly higher activity (steps/h) compared with the CTR group. Daily lying bouts tended to be higher for the OS group compared with CTR group in the first week of treatment. The overall results of this study documented that overstocking during the dry period was associated with a short-term changes in DHEA and cortisol but these hormonal modifications did not influence cow behavior

Effect of ewe diet on milk and muscle fatty acid composition of suckling lambs of the protected geographical origin abbacchio romano

Consumers increasingly pay more attention to the lipid profile of meat products and consume less meat to reduce cholesterol and heart disease. In Italy, sheep producers are increasingly feeding sheep fresh forage. We investigated whether the supplementation of dam diet with extruded linseed would be an alternative strategy to pasture for improving the intramuscular and subcutaneous FA compositions of their suckling lambs. The ewe diets were enriched with either extruded linseed (L), un-supplemented farm diet (F), or pasture (P). Milk saturated fatty acids (SFA) decreased in P and L compared with F, while the opposite pattern was observed for polyunsaturated FA (PUFA) and conjugated linoleic acids after seven days. The FA composition of lamb meat was similar to that of their dam\u2019s milk, showing higher PUFA in P and L compared to F, while SFA was higher in F. Regarding the lamb meat obtained from barn-held ewes, L had lower n-6/n-3 content compared to F, while an intermediate content was found in P. These results indicate a better n-3 FA profile in milk and lamb\u2019s meat from pasture and linseed-enriched diets. No changes in lamb performance were observed

The accuracy of NIRS in predicting chemical composition and fibre digestibility of hay-based total mixed rations

The aim of this study was to develop near-infrared spectroscopy (NIRS) prediction models for the estimation of chemical components and the fibre undegradable fractions (uNDF) of hay-based total mixed rations (TMR). A total of 205 TMR samples were used for the study. All the chemical components were measured using standard AOAC reference methods and expressed as percentages of dry matter (DM). Prediction models were developed using both cross- and independent validation and different mathematical treatments applied on spectral data. The best spectral treatment was chosen based on the method which simultaneously achieved the lowest root mean square error and the highest explained variance in cross-validation. The coefficient of determination in external validation (R2P) was the greatest for starch prediction model (R2P = 0.84), followed by acid detergent fibre (ADF; R2P = 0.79), and amylase-treated ash-corrected NDF with addition of sodium sulphite (aNDFom) and crude protein prediction models (CP; R2P = 0.73). The concordance correlation coefficient (CCC) in validation ranged from 0.66 (ash prediction model) to 0.92 (starch prediction model), indicating substantial to accurate models’ predictive ability. This study indicated that NIRS can be a screening method for the prediction of CP, Starch, aNDFom, ADF, acid detergent lignin (ADL), uNDF and Ash. The use of TMR utilised in various herds provided high variability for the NIRS calibration dataset, implying that the developed NIRS pre-diction models could be applicable to TMR collected from herds located in the Parmigiano Reggiano cheese production area.Highlights NIRS can be successfully employed to determine quickly and at cost-effective different compositional and digestibility traits in hay-based TMR. TMR analysis predicted by NIRS can support nutritionists in the formulation of diets containing a proper nutrient profile to sustain physiological, metabolic, and immunological processes. The use of NIR technology for TMR analysis can allow frequent monitoring of rations and increasingly timely corrections, maximising cows’ diet utilisation and conversion of the ingested feed

In vitro evaluation of sugar digestibility in molasses

Beet and cane molasses mainly contain mono- di-, and tri-saccharides, composed by hexoses, as well as pentoses in traces. However, rationing software consider sugars as only one entity, with a rate of digestion ∼20% h−1. The aim of this initial study was to investigate and evaluate the in vitro digestion dynamics and rates of the sugar fraction in molasses. Three beet and three cane molasses were randomly selected from a variety of samples collected world-wide and digested via in vitro rumen fermentation, at 1, 2, 3, 4, 6, 8, and 24 h. Samples were then analysed with a specific enzymatic kit to quantify residual sucrose, glucose, fructose, raffinose, galactose, and arabinose. Complete disappearance of sucrose happened within 3 hours of incubation. Glucose and fructose were completely digested within 4-6 h, showing variability among samples. Even if not so representative, galactose showed a similar trend of digestion (97% digestion within 3-4 h). Raffinose was quite slower in cane molasses, while it was completely digested within 1 h in beet molasses. Arabinose, a pentose, never reached a complete digestion, and its fermentation dynamic was different compared to other sugars. Calculated rates of digestion for sucrose, glucose and fructose, most representative sugars in molasses, were higher than 50% h−1 in both cane and beet. Obtained results showed that sugar fraction in molasses may vary, and different sugars are rapidly fermented by rumen microbes. Modern rationing models should consider a modification of sugar rates of digestion, since the actual one appears too slow than those observed in vitro.Highlights Molasses are unique blends of several sugars Major sugars are digested in few hours Rationing software should consider a faster rate of digestion for different sugars

Androgens and Adipose Tissue in Males: A Complex and Reciprocal Interplay

Clinical evidence shows that in males obesity is frequently associated with hypogonadism and vice versa; also, low testosterone levels have been considered a “hallmark” of metabolic syndrome in men. These observations indicate that there is a strict connection between anatomically and functionally distinct cell types such as white adipocytes and Leydig cells, that synthesize testosterone. Adipose tissue is able to control several functions of the testis through its products secreted in the bloodstream. On the other hand, circulating levels of testosterone and estradiol deeply affect adipocyte proliferation, differentiation, and fat mass distribution, hereby controlling critical metabolic functions, such as food intake, insulin sensitivity, vascular reactivity, and immunity. This paper highlights the existing clinical and experimental evidence linking androgens and adipose tissue and illustrates the consequences occurring when the balance between fat mass distribution and eugonadism is lost