Mid-Term Outcomes After Conversion Procedures Following Laparoscopic Sleeve Gastrectomy.

PURPOSE: In the long term, laparoscopic sleeve gastrectomy (SG) may be associated with insufficient weight loss (IWL), gastroesophageal reflux disease (GERD), and persistence or relapse of associated medical problems. This study's objective is to present mid-term results regarding weight loss (WL), evolution of associated medical problems, and reoperation rate of patients who underwent a conversion after SG. METHODS: Retrospective single-center analysis of patients with a minimal follow-up of 2 years after conversion. RESULTS: In this series of 549 SGs, 84 patients (15.3%) underwent a conversion, and 71 met inclusion criteria. They were converted to short biliopancreatic limb Roux-en-Y gastric bypass (short BPL RYGB) (n = 28, 39.4%), biliopancreatic diversion with duodenal switch (BPD/DS) (n = 19, 26.8%), long biliopancreatic limb Roux-en-Y gastric bypass (long BPL RYGB) (n = 17, 23.9%), and re-sleeve gastrectomy (RSG) (n = 7, 9.9%). Indications were GERD (n = 24, 33.8%), IWL (n = 23, 32.4%), IWL + GERD (n = 22, 31.0%), or stenosis/kinking of the sleeve (n = 2, 2.8%). The mean pre-revisional body mass index (BMI) was 38.0 ± 7.5 kg/m2. The mean follow-up time after conversion was 5.1 ± 3.1 years. The overall percentage of total weight loss (%TWL) was greatest after BPD/DS (36.6%) and long BPL RYGB (32.9%) compared to RSG (20.0%; p = 0.004; p = 0.049). In case of GERD, conversion to Roux-en-Y gastric bypass (RYGB) led to a resolution of symptoms in 79.5%. 16.9% of patients underwent an additional revisional procedure. CONCLUSION: In the event of IWL after SG, conversion to BPD/DS provides a significant and sustainable additional WL. Conversion to RYGB leads to a reliable symptom control in patients suffering from GERD after SG.

Long-term outcome after biliopancreatic diversion with duodenal switch: a single-center experience with up to 20 years follow-up.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD/DS) is the most effective standard bariatric procedure in terms of weight loss and remission of co-morbidities but carries the risk of severe long-term side effects. OBJECTIVE: The aim of this study was to analyze the long-term effects of BPD/DS in terms of morbidity, weight loss, remission of associated medical problems, deficiencies, and reoperations. SETTING: Academic teaching hospital, Switzerland. METHODS: This is a retrospective, single-center study of prospectively collected data of all patients who underwent BPD/DS from 1999 to 2011 with a minimal follow-up (FU) of 10 years. RESULTS: A total of 116 patients (83.6% female) underwent BPD/DS with a mean initial body mass index (BMI) of 47 ± 6.5 kg/m2. Of these, 68% of the procedures were performed in open technique and 32% laparoscopically. The majority (76.7%) of patients had laparoscopic adjustable gastric banding before BPD/DS. The mean FU time was 14 ± 4.4 years and the FU rate at 5, 10, and 14 years was 95.6% (n = 108), 90% (n = 98), and 75.3% (n = 70), respectively. The mean excess BMI loss at 5, 10, and 14 years was 78% ± 24.1%, 76.5% ± 26.7%, and 77.8% ± 33.8%, respectively. Complete (n = 22) or partial remission (n = 4) of type 2 diabetes was observed in 92.8% of patients. Forty reoperations were necessary in 34 patients (29.3%) because of malnutrition or refractory diarrhea (n = 13), insufficient weight loss or weight rebound (n = 7), reflux or stenosis (n = 10), and various/combined indications (n = 10). The mean time to reoperation was 7.7 ± 5 years. There were no procedure-related deaths in the short or long term. CONCLUSIONS: BPD/DS offers sustainable long-term weight loss but is associated with important side effects that may be acceptable in selected patients with a high initial BMI (>50 kg/m2) and/or for nonresponders after primary restrictive procedures. Regular FU is necessary to detect and treat malnutrition and vitamin deficiencies.

Management of gallstone disease prior to and after metabolic surgery: a single-center observational study.

BACKGROUND: Rapid weight loss after bariatric surgery is a risk factor for gallstone formation. There are different strategies regarding its management in bariatric patients, including prophylactic cholecystectomy (CCE) in all patients, concomitant CCE only in symptomatic patients, or concomitant CCE in all patients with known gallstones. We present the safety and long-term results of the last concept. METHOD: Retrospective single-center analysis of a prospective database on perioperative and long-term results of patients with laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) over a 15-year period. The minimal follow-up was 24 months. Concomitant CCE was intended for all patients with gallstones detected by preoperative sonography. SETTING: Academic teaching hospital in Switzerland. RESULTS: After exclusion of patients with a history of CCE (11.5%), a total of 1174 patients (69.6% LRYGB, 30.4% LSG) were included in the final analysis. Preoperative gallbladder pathology was detected in 21.2% of patients, of whom 98.4%, or 20.9% of the total patients, received a concomitant CCE. The additional procedure prolonged the average operation time by 38 minutes (not significant) and did not increase the complication rate compared with bariatric procedure without CCE (3.7% versus 5.7%, P = .26). No complication was directly linked to the CCE. Postoperative symptomatic gallbladder disease was observed in 9.3% of patients (LRYGB 7.0% versus LSG 2.3%, P = .15), with 19.8% of those patients initially presenting with a complication. CONCLUSION: The concept of concomitant CCE in primary bariatric patients with gallstones was feasible and safe. Nevertheless, 9.3% of primary gallstone-free patients developed postoperative symptomatic gallbladder disease and required subsequent CCE despite routine ursodeoxycholic acid prophylaxis.

Long-term Effects of Laparoscopic Sleeve Gastrectomy: What Are the Results Beyond 10 Years?

PURPOSE: Laparoscopic sleeve gastrectomy (LSG) has become the most commonly performed bariatric procedure worldwide. Newer studies providing long-term follow-up show a high incidence of weight regain and a high incidence of reflux. The study's objective was to present 5 to 15-year follow-up results regarding weight loss, comorbidities, reoperation rate, and a potential learning curve. METHODS: This is a retrospective analysis of prospectively collected data. Patients who underwent LSG between August 2004 and December 2014 were included. RESULTS: A total of 307 patients underwent LSG either as a primary bariatric procedure (n = 262) or as a redo operation after failed laparoscopic gastric banding (n = 45). Mean body mass index at the time of primary LSG was 46.4 ± 8.0 kg/m2, and mean age at operation was 43.7 ± 12.4 years with 68% females. Follow-up was 84% and 70% at 5 and 10 years, respectively. The mean percentage excess body mass index loss (%EBMIL) for primary LSG was 62.8 ± 23.1% after 5 years, 53.6 ± 24.6% after 10 years, and 51.2 ± 20.3% after 13 years. Comorbidities improved considerably (e.g., type 2 diabetes mellitus 61%), while the incidence of new-onset reflux was 32.4%. Reoperation after LSG was necessary in almost every fifth LSG-patient: 24 patients (7.8%) were reoperated due to insufficient weight loss, 12 patients (3.9%) due to reflux, 23 due to both (7.5%). CONCLUSIONS: LSG provides a long-term %EBMIL from 51 to 54% beyond 10 years and a significant improvement of comorbidities. On the other hand, a high incidence of insufficient weight loss and de novo reflux was observed, leading to reoperation and conversion to a different anatomy in 19.2%.

Preoperative Cardiac Diagnostics in Bariatric Patients with Diabetes and Perioperative Morbidity: Results of a Cohort of 258 Patients.

PURPOSE: The combination of obesity and diabetes mellitus are well-known risk factors for cardiovascular complications and perioperative morbidity in metabolic surgery. The aim of this study was to evaluate effectivity and reliability of the cardiac assessment in patients with diabetes prior to bariatric surgery. SETTING: Private, university-affiliated teaching hospital, Switzerland MATERIAL AND METHODS: Retrospective analysis of prospectively collected data on results and consequences of cardiac assessments in 258 patients with obesity and diabetes scheduled for primary bariatric surgery at our institution between January 2010 and December 2018. RESULTS: Out of 258 patients, 246 (95.3%) received cardiac diagnostics: 173 (67.1%) underwent stress-rest myocardial perfusion scintigraphy (MPS), 15 (5.8%) patients had other cardiac imaging including cardiac catheterization, 58 (22.5%) patients had echocardiography and/or stress electrocardiography, and 12 (4.7%) patients received no cardiac evaluation. Subsequently, cardiac catheterization was performed in 28 patients (10.9%), and coronary heart disease was detected and treated in 15 subjects (5.8%). Of these 15 individuals, 5 (33.3%) patients had diffuse vascular sclerosis, 8 (53.3%) patients underwent coronary angioplasty and stenting, and 2 (13.3%) patients coronary artery bypass surgery. Bariatric surgery was performed without perioperative cardiovascular events in all 258 patients. CONCLUSION: Our data suggest that a detailed cardiac assessment is mandatory in bariatric patients with diabetes to identify those with yet unknown cardiovascular disease before performing bariatric surgery. We recommend carrying out myocardial perfusion scintigraphy as a reliable diagnostic tool in this vulnerable population. If not viable, stress echocardiography should be performed as a minimum.

Outcome of revisional bariatric surgery for insufficient weight loss after laparoscopic Roux-en-Y gastric bypass: an observational study.

BACKGROUND: Insufficient weight loss or secondary weight regain with or without recurrence of comorbidity can occur years after laparoscopic Roux en Y gastric bypass (LRYGB). In selected patients, increasing restriction or adding malabsorption may be a surgical option after conservative measures failed. OBJECTIVES: Evaluation of short and long term results of revisional surgery for insufficient weight loss or weight regain after LRYGB. SETTING: Tertiary hospital. METHODS: Retrospective analysis of prospectively collected data from a cohort of 1150 LRYGB patients. Included were patients, who underwent revisional bariatric surgery after LRYGB for insufficient weight loss with a follow-up of minimal 1 year. RESULTS: Fifty-four patients were included in the analysis. After an interdisciplinary evaluation, patients with insufficient weight loss, signs of dumping syndrome, and lacking restriction were offered a nonadjustable band around the pouch (banded group, n = 34) and patients with sufficient restriction, excellent compliance, and adherence were offered a revision to laparoscopic biliopancreatic diversion (BPD group, n = 20). The revisional procedure was performed 3.3 ± 2.3 years after LRYGB in the banded-group and after 6.4 ± 4.3 years in the BPD group (P = .001). Mean body mass index at the time of the primary bariatric procedure was 41.7 ± 6.2 kg/m2 in the banded group and 45.2 ± 8.2 kg/m2 in the BPD group (P = .08); minimal body mass index between both operations was 29.1 ± 4.7 kg/m2 in the banded group and 36.5 ± 9.4 kg/m2 in the BPD group, and, at the time of revisional surgery, 31.4 ± 5.5 kg/m2 in the banded group and 40.8 ± 6.7 kg/m2 in the BPD group (P = .0001). The mean body mass index difference 1 year after revisional surgery was 1.3 ± 3.0 kg/m2 in the banded group and 6.7 ± 4.5 kg/m2 in the BPD group (P = .01). In the banded group, 11 patients (32.4%) needed removal of the band, 4 patients (11.8%) needed an adjustment, and 4 patients (11.8%) were later converted to BPD. In the BPD group, 2 (10.0%) patients needed revision for severe protein malabsorption. CONCLUSIONS: Insufficient weight loss or secondary weight regain after LRYGB is a rare indication for revisional surgery. Banded bypass has modest results for additional weight loss but can help patients suffering from dumping. In very carefully selected cases, BPD can achieve additional weight loss with acceptable complication rate but higher risk for reoperation. Future "adjuvant medical treatments," such as glucagon-like peptide 1 analogues and other pharmacologic treatment options could be an alternative for achieving additional weight loss and better metabolic response.

Long-term outcome of laparoscopic adjustable gastric banding (LAGB): results of a Swiss single-center study of 405 patients with up to 18 years' follow-up.

BACKGROUND: In the past, laparoscopic adjustable gastric banding (LAGB) seemed to be a promising bariatric procedure. However, many studies showed high rates of reoperation due to complications or insufficient weight loss. There is a lack of long-term studies with follow-up beyond 15 years. OBJECTIVE: To conduct long-term follow-up of patients after LAGB and analyze their weight loss as a primary endpoint. SETTING: Tertiary referral center for bariatric surgery, St. Claraspital, Switzerland. METHODS: A retrospective analysis of prospectively collected clinical data in a cohort of 405 patients having undergone LAGB was performed. RESULTS: A total of 405 patients (age 41±10 years, body mass index [BMI] 44.3±6 kg/m2) were treated with LAGB between 1996 and 2010. Mean follow-up was 13±3 years, with a follow-up rate of 85% (range 8-18 years), corresponding to 343 patients. One hundred patients exceeded 15-year follow-up. In 216 patients (63%), sleeve gastrectomy, gastric bypass, or biliopancreatic diversion with duodenal switch was performed as revisional surgery. Twenty-seven patients (8%) refused revisional surgery after band removal. Finally, 100 patients (29%) still have the band in place, with a mean BMI of 35±7 kg/m2, corresponding to an excess BMI loss of 48±27%. Among these, the failure rate was 25%, according to the Bariatric Analysis and Reporting Outcome System (BAROS); 50% had a good to excellent outcome. CONCLUSION: More than 10 years after LAGB, 71% of patients lost their bands and only 15% of the 343 followed patients with the band in place have a good to excellent result, according to BAROS.

Linear compared to circular stapler anastomosis in laparoscopic Roux-en-Y gastric bypass leads to comparable weight loss with fewer complications: a matched pair study.

OBJECTIVE: In the course of laparoscopic Roux-en-Y gastric bypass (LRYGB), a tight gastroenterostomy (GE) may lead to higher weight loss but possibly to an increase of local complications such as strictures and ulcers. Different operative techniques for Roux-en-Y reconstruction may also influence the rate of internal hernias, a typical late complication of LRYGB. The objective of this study was to compare weight loss, rates of strictures, internal hernias, and ulcerations of linear versus circular stapler anastomosis. METHODS: Retrospective analysis of prospectively collected data in a 3:1-matched pair study. A total of 228 patients with a minimal follow-up of 2 years were matched according to BMI at baseline, age, and gender. The follow-up rate was 100 % at 1 and 2 years postoperatively; the mean follow-up time was 3.8 ± 1.63 years. In group C (circular), 57 patients were operated with a 25-mm circular stapler technique (average BMI 44.7 ± 5.18 kg/m(2), age 44.1 ± 10.8 years, 80.7 % female). In group L (linear), 171 patients were operated using a linear stapler (approximately 30 mm, average BMI 43.8 ± 5.24 kg/m(2), age 43.7 ± 12.5 years, 70.8 % female). A propensity score matching and a logrank test were used for statistical analysis. RESULTS: The average excessive BMI loss (EBMIL) after 1 year was not statistically different (70.6 ± 20.2 % in group C vs 72.5 ± 20.4 % in group L) as well as after 2 years (71.6 ± 22.5 % in group C vs 74.6 ± 19.6 % in group L). The average operation time was 155 ± 53 min in group C and 109 ± 57 min in group L (p = 0.0001). In group L, patients had significantly lower overall stricture rates at the GE compared to group C (0 [0 %] vs. 4 [7 %], p = 0.0004), a lower rate and severity of internal hernias (10 [5.8 %] vs. 7 [12.3 %] p = 0.466), and equal local ulcerations rates (3 [1.8 %] vs. 1 [1.8 %] p = 0.912). CONCLUSION: Linear stapler anastomosis in LRYGB compared to circular anastomosis leads to equal weight loss and less strictures. The lower rate of internal hernias in linear stapler anastomosis was not significantly different.

Laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass lead to equal changes in body composition and energy metabolism 17 months postoperatively: a prospective randomized trial.

BACKGROUND: Weight loss is the sum of fat and lean mass loss. The aim of this study was to examine whether there are differences between 2 surgical procedures, laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB), in terms of their effect on body composition and energy metabolism. In addition, the predictive value of preoperative body composition and energy metabolism on postoperative outcome was evaluated. SETTING: All procedures were performed by the same surgeon (RP) at the St. Claraspital Basel in Switzerland. Calorimetry and DEXA were carried out at the same institution (Interdisciplinary Center of Nutritional and Metabolic Diseases, St. Claraspital Basel). METHODS: Forty-two morbidly obese, mainly female (85%), nondiabetic and diabetic (50%) patients (body mass index [BMI]: 43.9 kg/m(2)±1.3) before and 17±5.6 months after LSG (n = 23) and LRYGB (n = 19) were examined. Body composition was analyzed by dual-energy X-ray absorptiometry (DEXA) and resting energy expenditure (REE); fat and carbohydrate oxidation was determined by indirect calorimetry. RESULTS: Follow-up was 100%. Excessive BMI loss (EBMIL) was 64.4% in the LSG group and 76.4% in the LRYGB group (P<.046). In both groups total fat and muscle mass decreased significantly compared with baseline (P<.001) and the percentage of muscle mass per kilogram of weight increased postoperatively (results not significant). REE decreased (P<.001) and REE per kilogram of weight increased significantly (P<.003) compared with baseline. Carbohydrate oxidation remained stable in both groups, and fat oxidation decreased significantly (P<.001) compared with baseline. In diabetic patients compared with nondiabetic patients there were no statistically significant differences in REE, substrate oxidation, or reduction in truncal fat. Postoperatively, lean mass was higher in diabetic patients (P = .037). Preoperative indirect calorimetry and DEXA results were of no predictive value for outcome. CONCLUSION: Changes in REE and body composition were equal after both procedures in a bariatric population mainly consisting of women. No predictors for amount of weight loss could be found.

Five-year results of laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is gaining popularity, but studies reporting long-term results are still rare. The objective of this study was to present the 5-year outcome concerning weight loss, modification of co-morbidities, and late complications. METHODS: This is a retrospective analysis of a prospective cohort with a minimal follow-up of 5 years. A total of 68 patients underwent LSG either as primary bariatric procedure (n = 41) or as redo operation after failed laparoscopic gastric banding (n = 27) between August 2004 and December 2007. At the time of LSG, the mean body mass index (BMI) was 43.0 ± 8.0 kg/m(2), the mean age 43.1 ± 10.1 years, and 78% were female. The follow-up rate was 100% at 1 year postoperatively, 97% after 2 years, and 91% after 5 years; the mean follow-up time was 5.9 ± 0.8 years. RESULTS: The average excessive BMI loss was 61.5% ± 23.4% after 1 year, 61.1% ± 23.4% after 2 years, and 57.4% ± 24.7% after 5 years. Co-morbidities improved considerably; a remission of type 2 diabetes could be reached at 85%. The following complications were observed: 1 leak (1.5%), 2 incisional hernias (2.9%), and new-onset gastroesophageal reflux in 11 patients (16.2%). Reoperation due to insufficient weight loss was necessary in 8 patients (11.8%). CONCLUSIONS: LSG was effective 5.9 years postoperatively with an excessive BMI loss of almost 60% and a considerable improvement or even remission of co-morbidities.

Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity.

The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature.

CONTEXT: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported. OBJECTIVE: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS: Fifty-seven patients who underwent surgery for benign adrenal tumors were included in this study. MAIN OUTCOME MEASURES: Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by uncoupling protein 1 (UCP1) protein and mRNA expression was measured. RESULTS: Using protein and mRNA expression analysis, we detected UCP1 protein in 26 of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression on both mRNA and protein level was inversely correlated to outdoor temperature, whereas body mass index, sex, age, and diabetes status were not. CONCLUSIONS: These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance.

Evidence for two types of brown adipose tissue in humans.

The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.

Lipocalin prostaglandin D synthase and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism in vivo.

Mice lacking Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) have unexpectedly normal glucose tolerance and mild insulin resistance. Mice lacking PPARγ2 were found to have elevated levels of Lipocalin prostaglandin D synthase (L-PGDS) expression in BAT and subcutaneous white adipose tissue (WAT). To determine if induction of L-PGDS was compensating for a lack of PPARγ2, we crossed L-PGDS KO mice to PPARγ2 KO mice to generate Double Knock Out mice (DKO). Using DKO mice we demonstrated a requirement of L-PGDS for maintenance of subcutaneous WAT (scWAT) function. In scWAT, DKO mice had reduced expression of thermogenic genes, the de novo lipogenic program and the lipases ATGL and HSL. Despite the reduction in markers of lipolysis in scWAT, DKO mice had a normal metabolic rate and elevated serum FFA levels compared to L-PGDS KO alone. Analysis of intra-abdominal white adipose tissue (epididymal WAT) showed elevated expression of mRNA and protein markers of lipolysis in DKO mice, suggesting that DKO mice may become more reliant on intra-abdominal WAT to supply lipid for oxidation. This switch in depot utilisation from subcutaneous to epididymal white adipose tissue was associated with a worsening of whole organism metabolic function, with DKO mice being glucose intolerant, and having elevated serum triglyceride levels compared to any other genotype. Overall, L-PGDS and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism.

Isoenergetic feeding of low carbohydrate-high fat diets does not increase brown adipose tissue thermogenic capacity in rats.

UNLABELLED: Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in overweighed adults. Adaptive thermogenesis increased by specific effects of macronutrients on energy expenditure has been postulated to induce this weight loss. We studied brown adipose tissue (BAT) morphology and function following exposure to different LC-HF diets. METHODS: Male Wistar rats were fed a standard control diet ad libitum or pair-fed isoenergetic amounts of three experimental diets for 4 weeks. The diets had the following macronutrient composition (% metabolizable energy: carbohydrates, fat, protein): control (64.3/16.7/19), LC-HF-low protein (LC-HF-LP, 1.7/92.8/5.5), LC-HF-normal-protein (LC-HF-NP, 2.2/78.7/19.1), and a high fat diet with carbohydrates ("high fat", 19.4/61.9/18.7). RESULTS: Body weight gain was reduced in all pair-fed experimental groups as compared to rats fed the control diet, with more pronounced effect in rats on LC-HF diets than on the high fat diet with carbohydrates. High fat diets increased expression of PGC1α and ADRB3 in BAT indicating higher SNS outflow. However, UCP1 mRNA expression and expression of UCP1 assessed by immunohistochemistry was not different between diet groups. In accordance, analysis of mitochondrial function in-vitro by extracellular flux analyser (Seahorse Bioscience) and measurement of inducible thermogenesis in vivo (primary endpoint), explored by indirect calorimetry following norepinephrine injection, did not show significant differences between groups. Histology of BAT revealed increased lipid droplet size in rats fed the high-fat diet and both LC-HF diets. CONCLUSION: All experimental diets upregulated expression of genes which are indicative for increased BAT activity. However, the functional measurements in vivo revealed no increase of inducible BAT thermogenesis. This indicates that lower body weight gain with LC-HF diets and a high fat diet in a pair-feeding setting is not caused by increased adaptive thermogenesis in BAT.

BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions.

Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

Short-term exposure to low-carbohydrate, high-fat diets induces low bone mineral density and reduces bone formation in rats.

Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in adults and are also used as part of a treatment for children with epilepsy. However, potential risks and side effects remain controversial. We investigated effects of LC-HF diets on growth, bone mineral density (BMD), and turnover in growing rats fed for 4 weeks either normal chow (CH, 9% fat, 33% protein, and 58% carbohydrates), LC-HF-1 (66% fat, 33% protein, and 1% carbohydrates), or LC-HF-2 (94.5% fat, 4.2% protein, and 1.3% carbohydrates). Rats fed LC-HF diets accumulated significantly more visceral and bone marrow fat and showed increased leptin but decreased insulin-like growth-factor 1 (IGF-1). Both LC-HF diets significantly decreased body length (nose to rump), but lengths of humerus, tibia, and femur were significantly reduced with LC-HF-2 only. Peripheral quantitative computed tomography (pQCT) and micro-CT (microCT) independently revealed significant reductions in BMD of tibiae in both LC-HF groups, and tibial maximum load was impaired. Bone-formation marker N-terminal propeptide of type I procollagen was reduced in sera of LC-HF groups, whereas bone resorption marker CrossLaps remained unchanged. Real-time PCR analysis revealed significant reductions by 70% to 80% of transcription factors influencing osteoblastogenesis (Runx2, osterix, and C/EBPbeta) in bone marrow of rats fed LC-HF diets. In conclusion, both LC-HF diets impaired longitudinal growth, BMD, and mechanical properties, possibly mediated by reductions in circulating IGF-1. Serum bone-formation markers as well as expression of transcription factors influencing osteoblastogenesis were reduced. This might indicate a lower rate of mesenchymal stem cells differentiating into osteoblasts, thus explaining reduced bone formation with LC-HF diets.

Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine.

BACKGROUND: Dosage of T(4) in central hypothyroidism is primarily guided by the free serum T(4) level (fT4). However, the optimum fT4 range is ill defined, and subtle hypothyroidism might be missed using this approach. OBJECTIVES: Our aim was to investigate the effects of a body weight (bw)-adapted T(4) treatment, alone or in combination with T(3), on metabolism, well-being, and cognitive function in comparison to a regimen leading to normal fT4. DESIGN: This was a placebo-controlled trial (double-blind, crossover). PATIENTS: A total of 29 patients (age 52 +/- 2 yr; females/males, 8/21) with hypopituitarism, including TSH deficiency, participated in the study. INTERVENTIONS: Three regimens were compared (5 wk each): "EMPIRICAL-T4," empirical T(4) dosage (1 +/- 0.05 microg/kg bw) leading to normal fT4; BW-ADAPTED-T4 (1.6 microg/kg bw T(4)); and "BW-ADAPTED-T3T4," bw-adapted combination of T(3) and T(4) (ratio of 1:10). RESULTS: BW-ADAPTED-T4 administration increased mean fT4 concentrations to the upper limit of the normal range (peak levels). Compared with EMPIRICAL-T4, BW-ADAPTED-T4 treatment resulted in a lower body mass index (BMI) (29.0 +/- 0.7 vs. 29.5 +/- 0.7 kg/m(2); P < 0.03), lower total cholesterol (198 +/- 9 vs. 226 +/- 7 mg/dl; P < 0.01), and lower low-density lipoprotein (LDL) cholesterol (116 +/- 5 vs. 135 +/- 7 mg/dl; P < 0.01). BW-ADAPTED-T3T4 treatment was associated with additional beneficial effects on ankle reflex time and working memory but resulted in supraphysiological free serum T(3) (fT(3)) levels. LIMITATIONS: Long-term side effects may have been missed. CONCLUSIONS: Using a dose of 1.6 microg/kg bw improved markers commonly associated with central hypothyroidism. This suggests that T(4) dosage based on bw and aiming at fT4 in the upper reference range is superior to titration of T(4) aiming at middle normal fT4 concentrations in those patients.