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Bajor A.,Sahlgrenska Academy | Tornblom H.,Sahlgrenska Academy | Tornblom H.,Gothenburg University | Rudling M.,Metabolism Unit | And 4 more authors.

Objective: Bile acids may play a role in the pathogenesis of IBS. We investigated the potential effects of bile acids entering the colon and its role in the symptom pattern in IBS.Design: We measured75Se-labelled homocholic acidtaurine (75SeHCAT) retention, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor (FGF) 19 in patients with IBS (n=141) and control subjects (75SeHCAT n=29; C4 and FGF19 n=435). In patients with IBS stool frequency and form, as well as GI symptom severity were registered, and in a proportion of patients colonic transit time and rectal sensitivity were measured (n=66). An 8-week open-label treatment with colestipol was offered to patients with75SeHCAT <20%, and the effect of treatment was evaluated with IBS severity scoring system and adequate relief of IBS symptoms.Results: Compared with controls, patients with IBS had lower75SeHCAT values (p=0.005), higher C4c levels (C4 corrected for cholesterol) (p<0.001), but similar FGF19 levels. Abnormal75SeHCAT retention (<10%) was seen in 18% of patients, whereas 23% had elevated C4c levels. Patients with IBS with75SeHCAT retention <10% had more frequent stools, accelerated colonic transit time, rectal hyposensitivity, a higher body mass index, higher C4c and lower FGF19 levels. Colestipol treatment improved IBS symptoms (IBS severity scoring system 220 ±109 vs 277±106; p<0.01), and 15/27 patients fulfilled criteria for treatment response (adequate relief ≥50% of weeks 5-8).Conclusions: Increased colonic bile acid exposure influences bowel habit and colonic transit time in patients with IBS. A high response rate to open label treatment with colestipol supports this, but placebo-controlled studies are warranted. Source

Shinoda K.,University of California at San Francisco | Luijten I.H.N.,University of California at San Francisco | Luijten I.H.N.,University of Stockholm | Hasegawa Y.,University of California at San Francisco | And 17 more authors.
Nature Medicine

Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators. ©2005 Nature America, Inc. All rights reserved. Source

Selmi C.,Metabolism Unit | Selmi C.,University of California at Davis | Papini A.M.,University of Florence | Pugliese P.,Metabolism Unit | Gershwin M.E.,University of California at Davis
Archives of Medical Science

The pathways leading to autoimmunity remain enigmatic despite numerous lines of experimental inquiry and epidemiological evidence. The mechanisms leading to the initiation and perpetuation of specific diseases such as primary biliary cirrhosis (PBC) or multiple sclerosis (MS) remain largely enigmatic, although it is established that a combination of genetic predisposition and environmental stimulation is required. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins concur to support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity through different mechanisms. In the present article we illustrate the current hypotheses related to an environmental impact on the onset of PBC and MS as two representative conditions investigated with complementary approaches. Indeed, while a role of post-translational antigen modifications has been proposed for MS, this field remain unexplored in PBC where, conversely, most evidence is gathered from geoepidemiology and experimental data on xenobiotics or infectious agents. Copyright © 2011 Termedia & Banach. Source

Zijlmans W.C.W.R.,Pediatric Research Institute | Van Kempen A.A.M.W.,Onze Lieve Vrouwe Gasthuis | Serlie M.J.,Metabolism Unit | Sauerwein H.P.,Metabolism Unit
Journal of Pediatric Endocrinology and Metabolism

Hypoglycemia is a frequently encountered complication in young children with infectious diseases and may result in permanent neurological damage or even death. Mortality rate in young children under 5 years of age is increased four- to six-fold when severe infectious disease is complicated by hypoglycemia. Young age, prolonged fasting and severity of disease are considered important risk factors. This perspective describes the combined results of recently conducted studies on the effect of these risk factors on glucose metabolism in children with different infectious diseases. The results of these studies have nutritional implications for the approach in clinical practice towards young children with infectious diseases and specific recommendations are made. A unique finding is the existence of infectious disease-related differences in the adaptation of glucose metabolism during fasting in young children. Source

Cai H.,Metabolism Unit | Daimon C.M.,Metabolism Unit | Cong W.-N.,Metabolism Unit | Wang R.,Metabolism Unit | And 5 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences

Calorie restriction (CR) is a lifestyle intervention employed to reduce body weight and improve metabolic functions primarily via reduction of ingested carbohydrates and fats. Taste perception is highly related to functional metabolic status and body adiposity. We have previously shown that sweet taste perception diminishes with age; however, relatively little is known about the effects of various lengths of CR upon taste cell morphology and function. We investigated the effects of CR on taste bud morphology and expression of sweet taste-related modulators in 5-, 17-, and 30-month-old rats. In ad libitum (AL) and CR rats, we consistently found the following parameters altered significantly with advancing age: reduction of taste bud size and taste cell numbers per taste bud and reduced expression of sonic hedgehog, type 1 taste receptor 3 (T1r3), α-gustducin, and glucagon-like peptide-1 (GLP-1). In the oldest rats, CR affected a significant reduction of tongue T1r3, GLP-1, and α-gustducin expression compared with age-matched AL rats. Leptin receptor immunopositive cells were elevated in 17- and 30-month-old CR rats compared with age-matched AL rats. These alterations of sweet taste-related modulators, specifically during advanced aging, suggest that sweet taste perception may be altered in response to different lengths of CR. © 2013 Published by Oxford University Press. Source

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