Testosterone Reduces Body Fat in Male Mice by Stimulation of Physical Activity Via Extrahypothalamic ERα Signaling.

Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.

Reversal of Roux-en-Y Gastric Bypass Fails to Facilitate the Management of Recalcitrant Hypocalcaemia Caused by Primary Hypoparathyroidism.

Roux-en-Y gastric bypass (RYGB) is thought to reduce calcium absorption from the gut. Here, we report the case of a patient with a RYGB, who developed primary hypoparathyroidism after a total thyroidectomy, leading to recalcitrant hypocalcaemia. Despite aggressive oral calcium and calcitriol supplementation, she remained hypocalcaemic and required intravenous (IV) calcium supplementation to control her symptoms, and to keep calcium serum levels within an acceptable range. Teriparatide treatment improved calcium levels marginally. This treatment, however, was poorly tolerated and ultimately stopped by the patient. As a last resort, reversal of RYGB was performed to improve calcium absorption from the gut. Unfortunately, IV calcium supplementation remained necessary. This case illustrates that the reversal of RYGB is not always a guarantee for success in managing recalcitrant hypocalcaemia.

Involvement of the GHSR in the developmental programming and metabolic disturbances induced by maternal undernutrition.

The mismatch between maternal undernutrition and adequate nutrition after birth increases the risk of developing metabolic diseases. We aimed to investigate whether the hyperghrelinemia during maternal undernourishment rewires the hypothalamic development of the offspring and contributes to the conversion to an obese phenotype when fed a high-fat diet (HFD). Pregnant C57BL/6 J, wild type (WT) and ghrelin receptor (GHSR)-/- mice were assigned to either a normal nourished (NN) group, or an undernutrition (UN) (30% food restricted) group. All pups were fostered by NN Swiss mice. After weaning, pups were fed a normal diet, followed by a HFD from week 9. Plasma ghrelin levels peaked at postnatal day 15 (P15) in both C57BL/6 J UN and NN pups. Hypothalamic Ghsr mRNA expression was upregulated at P15 in UN pups compared to NN pups and inhibited agouti-related peptide (AgRP) projections. Adequate lactation increased body weight of UN WT but not of GHSR-/- pups compared to NN littermates. After weaning with a HFD, body weight and food intake was higher in WT UN pups but lower in GHSR-/- UN pups than in NN controls. The GHSR prevented a decrease in ambulatory activity and oxygen consumption in UN offspring during ad libitum feeding. Maternal undernutrition triggers developmental changes in the hypothalamus in utero which were further affected by adequate feeding after birth during the postnatal period by affecting GHSR signaling. The GHSR contributes to the hyperphagia and the increase in body weight when maternal undernutrition is followed by an obesity prone life environment.

The curious fate of bone following bariatric surgery: bone effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) in mice.

BACKGROUND: Bone loss and increased fracture risk following bariatric surgery has been reported. We investigated whether the two most commonly performed surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), lead to bone loss. In addition, we examined whether fortification of the diet with calcium citrate prevents bone loss. METHODS: We used mouse models for SG and RYGB and compared bone loss with a group of sham mice with similar weight loss. All groups were switched at the time of surgery to a low-fat diet (LFD). We also examined whether fortification of the diet with calcium citrate and vitamin D was able to prevent bone loss. RESULTS: At 2 weeks we observed no major bone effects. However, at 8 weeks, both trabecular and cortical bone were lost to the same extent after SG and RYGB, despite increased calcium absorption and adequate serum levels of calcium, vitamin D, and parathyroid hormone (PTH). Diet fortification with calcium citrate and vitamin D was able to partially prevent bone loss. CONCLUSIONS: Both SG and RYGB lead to excess bone loss, despite intestinal adaptations to increase calcium absorption. Fortifying the diet with calcium citrate and vitamin D partly prevented the observed bone loss. This finding emphasizes the importance of nutritional support strategies after bariatric surgery, but also affirms that the exact mechanisms leading to bone loss after bariatric surgery remain elusive and thus warrant further research.

Can Improved Legume Varieties Optimize Iron Status in Low- and Middle-Income Countries? A Systematic Review.

Iron and zinc deficiencies are some of the most widespread micronutrient deficiencies in low- and middle-income countries (LMIC). Dietary diversification, food fortification, nutrition education, and supplementation can be used to control micronutrient deficiencies. Legumes are important staple foods in most households in LMIC. Legumes are highly nutritious (good sources of essential minerals, fiber, and low glycemic index) and offer potential benefits in addressing nutrition insecurity in LMIC. Several efforts have been made to increase micronutrient intake by use of improved legumes. Improved legumes have a higher nutrient bioavailability, lower phytate, or reduced hard-to-cook (HTC) defect. We hypothesize that consumption of improved legumes leads to optimization of zinc and iron status and associated health outcomes. Therefore, the objective of this review is to examine the evidence on the efficacy of interventions using improved legumes. Nine relevant studies are included in the review. Consumption of improved legumes resulted in a ≥1.5-fold increase in iron intake. Several studies noted modest improvements in biomarkers of iron status [hemoglobin (Hb), serum ferritin (SF), and transferrin receptor] associated with consumption of improved legumes. Currently, no efficacy studies assessing the relation between consumption of improved legumes and zinc status are available in the literature. Evidence shows that, in addition to repletion of biomarkers of iron status, consumption of improved legumes is associated with both clinical and functional outcomes. The prevalence of iron deficiency (ID) decreases with consumption of improved legumes, with increases of ≤3.0 g/L in Hb concentrations. Improvement in cognition and brain function in women has been reported as well. However, further research is necessary in more at-risk groups and also to show if the reported improvements in status markers translate to improved health outcomes. Evidence from the included studies shows potential from consumption of improved legumes suggesting them to be a sustainable solution to improve iron status.

Predicting iron absorption from an effervescent iron supplement in obese patients before and after Roux-en-Y gastric bypass: a preliminary study.

BACKGROUND & AIMS: Oral iron absorption is hampered in obese and bariatric patients, especially after Roux-en-Y gastric bypass (RYGB). As a result, iron deficiency, which is common in both patient groups, can be difficult to treat by oral supplements, often necessitating a switch to parenteral administration. The aim of this study was to find possible predictors of the extent of absorption of an effervescent iron gluconate oral supplement, which enables to pre-emptively identify those patients in which oral supplementation is likely to fail. METHODS: The pharmacokinetic properties of 695 mg effervescent iron gluconate (80 mg Fe2+) were assessed in 13 obese patients (female = 10; mean age ± SD: 45.2 ± 12.5years) pre- and six months post-RYGB by measuring serum iron concentrations during 24 hours and by calculating the adjusted for baseline AUC0-24h, Cmax and Tmax. A multivariate regression analysis was performed to investigate the effect of hepcidin concentration, iron and hematologic indices, personal and anthropometric characteristics on iron absorption. Subsequently, Receiver Operating Characteristic (ROC) curves were used to propose the cut-off value for hepcidin concentrations above which obese patients are unlikely to benefit from oral iron supplementation. Data are expressed as mean ± SD. RESULTS: Low iron status persisted after surgery as there was no significant difference observed in TSAT (17.3 ± 5.2 vs. 20.2 ± 6.6%), ferritin (91.8 ± 68.6 vs. 136.2 ± 176.9 µg/L) and hepcidin concentration (32.0 ± 30.1 vs. 28.3 ± 21.3 ng/mL) after RYGB. The absorption of effervescent iron gluconate was similar pre- and post-RYGB [AUC0-24h,pre-RYGB: 28.6 ± 10.8 µg/dL*h; AUC0-24h,post-RYGB: 27.5 ± 9.11 µg/dL*h (P = 0.84)]. Post-RYGB, iron AUC0-24h showed a strong negative correlation with both hepcidin concentrations and TSAT (R=-0.51; P = 0.08 and R=-0.81; P = 0.001), respectively. Pre-RYGB, there was a clear trend for the same negative correlations for hepcidin concentrations and TSAT (R=-0.47; P = 0.11 ;R=-0.41; P = 0.16), respectively. Taking pre-and post-RYGB data together, the negative correlations were confirmed for hepcidin concentrations and TSAT (R=-0.54; P = 0.004; R=-0.60; P = 0.001), respectively. The AUCROC = 0.87 (95%CI 0.71; 1.00) showed an optimal sensitivity/specificity cut-off at hepcidin concentrations of 26.8 ng/mL. CONCLUSIONS: The iron AUC0-24h showed a negative correlation with the hepcidin concentration and TSAT of obese patients, in particular post-RYGB. Therefore, our data support the use of hepcidin concentration and TSAT to distinguish potential responders from non-responders for iron supplementation particularly post-RYGB. Additionally, this study showed that the pharmacokinetic properties of iron gluconate from an effervescent tablet were unaffected by RYGB-surgery.

Micronutrient intake, from diet and supplements, and association with status markers in pre- and post-RYGB patients.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) is associated with an increased risk for micronutrient deficiencies. This study aimed to assess total (dietary and supplement) intake and association with iron (including hepcidin), vitamin B12, vitamin C and zinc status markers before and after Roux-en-Y gastric bypass (RYGB). METHODS: This prospective study included patients with a planned RYGB in University Hospitals Leuven, Belgium; who were followed until 12 months post-RYGB. Patients completed an estimated dietary record of two non-consecutive days before and 1, 3, 6 and 12 months post-RYGB and supplement/drug use was registered. Associations between total micronutrient intake and status markers were analyzed. RESULTS: Fifty-four patients (21 males; mean age: 48.0 [95%CI 46.6; 49.3] years; mean preoperative BMI: 40.4 [95%CI 39.4; 41.4] kg/m2) were included. One month post-RYGB, usual dietary intake of the studied micronutrients was significantly decreased compared to pre-RYGB, but gradually increased until 12 months post-RYGB, remaining below baseline values. By including micronutrient supplement intake, 12 months post-RYGB values were higher than baseline, except for zinc. Hemoglobin, ferritin, vitamin B12 and C-reactive protein serum concentrations were significantly decreased and transferrin saturation and mean corpuscular volume were significantly increased 12 months post-RYGB. Serum hepcidin concentration was significantly decreased 6 months post-RYGB. CONCLUSIONS: Medical nutritional therapy is essential following RYGB as dietary intake of iron, vitamin B12, vitamin C, copper and zinc was markedly decreased postoperatively and some patients still had an inadequate total intake one year post-RYGB.

AURORA: bariatric surgery registration in women of reproductive age - a multicenter prospective cohort study.

BACKGROUND: The expansion of the obesity epidemic is accompanied with an increase in bariatric procedures, in particular in women of reproductive age. The weight loss induced by the surgery is believed to reverse the negative impact of overweight and obesity on female reproduction, however, research is limited to in particular retrospective cohort studies and a growing number of small case-series and case-(control) studies. METHODS/DESIGN: AURORA is a multicenter prospective cohort study. The main objective is to collect long-term data on reproductive outcomes before and after bariatric surgery and in a subsequent pregnancy. Women aged 18-45 years are invited to participate at 4 possible inclusion moments: 1) before surgery, 2) after surgery, 3) before 15 weeks of pregnancy and 4) in the immediate postpartum period (day 3-4). Depending on the time of inclusion, data are collected before surgery (T1), 3 weeks and 3, 6, 12 or x months after surgery (T2-T5) and during the first, second and third trimester of pregnancy (T6-T8), at delivery (T9) and 6 weeks and 6 months after delivery (T10-T11). Online questionnaires are send on the different measuring moments. Data are collected on contraception, menstrual cycle, sexuality, intention of becoming pregnant, diet, physical activity, lifestyle, psycho-social characteristics and dietary supplement intake. Fasting blood samples determine levels of vitamin A, D, E, K, B-1, B-12 and folate, albumin, total protein, coagulation parameters, magnesium, calcium, zinc and glucose. Participants are weighted every measuring moment. Fetal ultrasounds and pregnancy course and complications are reported every trimester of pregnancy. Breastfeeding is recorded and breast milk composition in the postpartum period is studied. DISCUSSION: AURORA is a multicenter prospective cohort study extensively monitoring women before undergoing bariatric surgery until a subsequent pregnancy and postpartum period. TRIAL REGISTRATION: Retrospectively registered (July 2015 - NCT02515214 ).

Iron deficiency after Roux-en-Y gastric bypass: insufficient iron absorption from oral iron supplements.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) may reduce the absorption of iron, but the extent to which this absorption is impeded is largely unknown. First, we determined the prevalence of iron deficiency following RYGB and explored the risk factors for its development. Second, we examined to what extent oral iron supplements are absorbed after RYGB. METHODS: Monocentric retrospective study in 164 patients (123 females, 41 males; mean age 43 years) who underwent RYGB between January 2006 and November 2010 was done. Pre- and postoperative data on gender, age, BMI, serum levels of iron, ferritin, hemoglobin, vitamin B12, 25-hydroxy vitamin D, and use of proton pump inhibitors and H2 antagonists were collected. Generalized linear mixed models were used for the analysis of the data. In 23 patients who developed iron deficiency after surgery, an oral challenge test with 100 mg FeSO4 · 7H2O was performed. RESULTS: Following RYGB, 52 (42.3 %) female patients and 9 male (22.0 %) patients developed iron deficiency (serum ferritin concentration ≤ 20 µg/L). The prevalence of iron deficiency was significantly higher in females than males (p = 0.0170). Young age (p = 0.0120), poor preoperative iron status (p = 0.0004), vitamin B12 deficiency (p = 0.0009), and increasing time after surgery (p < 0.0001) were also associated with iron deficiency. In the oral iron challenge test, only one patient out of 23 showed sufficient iron absorption. CONCLUSIONS: Iron deficiency is extremely frequent after RYGB and is linked with different risk factors. Iron supplementation seems essential, but the effect of oral tablets may be limited as absorption of oral iron supplements is insufficient post-RYGB.

Straight from D-Heart: vitamin D status and cardiovascular disease.

PURPOSE OF REVIEW: To offer a comprehensive overview of the best available evidence linking vitamin D status, including the effect of vitamin D supplementation, to the risk of cardiovascular events. RECENT FINDINGS: There is an abundance of plausible mechanisms by which vitamin D might have a favorable effect on the cardiovascular risk profile in the general population. Epidemiological data strongly support such beneficial effects of vitamin D, but initial enthusiasm is giving way to skepticism as larger, well conducted, longitudinal observational trials fail to show an association between serum vitamin D levels and mortality from cardiovascular events. Moreover, the few existing prospective randomized controlled trials with vitamin D supplementation that report the incidence of cardiovascular events show no effect. Fortunately, larger and better designed prospective trials are underway. Nonetheless, one should also acknowledge that true vitamin D deficiency [<25 nmol/l (10 ng/ml)] remains prevalent in the general population and is convincingly associated with overall adverse outcomes. SUMMARY: Currently, robust clinical data are lacking to support raising intake requirements and target vitamin D plasma levels based on a role for vitamin D in preventing cardiometabolic diseases. Nonetheless, the high prevalence of vitamin D deficiency in the general population remains alarming and requires implementation of clear supplementation guidelines.