Metabolism Unit

San Francisco, CA, United States

Metabolism Unit

San Francisco, CA, United States
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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 | Year: 2014

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.


Zijlmans W.C.W.R.,Diakonessen Hospital | Van kempen A.A.M.W.,Onze Lieve Vrouwe Gasthuis | Sauerwein H.P.,Metabolism Unit
Journal of Tropical Pediatrics | Year: 2013

The objective of this study was to investigate glucose kinetics during controlled fasting in children with severe pneumonia. Plasma glucose concentration, endogenous glucose production and gluconeogenesis were measured in 12 Surinamese children (six young: 1-3 years, six older: 3-5 years) with severe pneumonia during a controlled 16 h fast using stable isotopes [6,6-2H2]glucose and 2H2O at a hospital-based research facility. On admission, the glucose concentrations were comparable in both groups: young children: 5.1 ± 1.3 mmol/l, older children: 4.8 ± 0.6 mmol/l, p = 0.685, with a decrease during the first 8 h of fasting in the young children only to 3.6 ± 0.5, p = 0.04. Glucose production was comparable in both groups: young: 24.5 ± 8.3, older: 24.9 ± 5.9 μmol/kgmin, p = 0.926. Between 8 and 16 h of fasting, the glucose concentration decreased comparably in both groups (young: - 0.9 ± 0.7, p = 0.004; older: -1.0 ± 0.4 mmol/l, p = 0.001), as did glucose production (young: -6.8 ± 6.3, p = 0.003; older: -5.3 ± 3.4 μmol/kgmin, p = 0.001). Gluconeogenesis decreased in young children only: -5.0 ± 7.4, p = 0.029. We conclude that fasting predisposes to hypoglycemia in children with severe pneumonia. Young children are more at risk than older children. Glucose production is an important determinant of the plasma glucose concentration in young children with pneumonia, indicating an inability to reduce glucose usage. Our results are largely in agreement with the literature on the adaptation of glucose metabolism in children with malaria, although there seem to be disease-specific differences in the regulation of gluconeogenesis. © The Author [2012]. Published by Oxford University Press. All rights reserved.


Zijlmans W.C.W.R.,Suriname Childrens Hospital Academic Hospital Paramaribo | 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 | Year: 2014

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.


PubMed | Southwest Research Institute, Metabolism Unit, Baylor College of Medicine, Johns Hopkins University and 9 more.
Type: Journal Article | Journal: Cell reports | Year: 2015

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.


Bajor A.,Sahlgrenska Academy | Tornblom H.,Sahlgrenska Academy | Tornblom H.,Gothenburg University | Rudling M.,Metabolism Unit | And 4 more authors.
Gut | Year: 2014

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.


Fram R.Y.,Metabolism Unit | Fram R.Y.,University of Texas Medical Branch | Fram R.Y.,Shriners Hospital for Children | Cree M.G.,Metabolism Unit | And 10 more authors.
Critical Care Medicine | Year: 2010

Objective: To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. Design: Prospective, randomized study. Setting: An acute pediatric burn unit in a tertiary teaching hospital. Patients: Children, 4-18 yrs old, with total body surface area burned ≥40% and who arrived within 1 wk after injury were enrolled in the study. Interventions: Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose ≤215 mg/dL. Measurements and main results: Twenty patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days postburn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 ± 124 to 1925 ± 291 kcal/m•day; p =.02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 ± 0.8 conventional insulin therapy vs. 6.8 ± 0.9 mg/kg•min intensive insulin therapy; p =.5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 ± 1.3 intensive insulin therapy versus 4.8 ± 0.6 mg/kg•min conventional insulin therapy, p =.005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 ± 0.9 vs. 2.5 ± 0.6 mg/kg•min; intensive insulin therapy vs. conventional insulin therapy; p =.03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 ± 0.1 to 1.7 ± 0.1 μm O2/CS/mg protein/min for state 3, p =.004; and 0.7 ± 0.1 to 1.3 ± 0.1 μm O2/CS/mg protein/min for state 4, p <.002), whereas conventional insulin therapy remained at the same level of activity (0.9 ± 0.1 to 0.8 ± 0.1.μm O2/CS/mg protein/min for state 3, p =.4; 0.6 ± 0.03 to 0.7 ± 0.1 μm O2/CS/mg protein/min, p =.6). Conclusion: Controlling blood glucose levels ≤120 mg/dL using an intensive insulin therapy protocol improves insulin sensitivity and mitochondrial oxidative capacity while decreasing resting energy expenditure in severely burned children. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Ghosh M.,Metabolism Unit | Ghosh M.,Molecular Nutrition Unit | Ghosh M.,Karolinska Institutet | Ghosh M.,Karolinska University Hospital | And 11 more authors.
Journal of Lipid Research | Year: 2015

Pharmacologically increased estrogen levels have been shown to lower hepatic and plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in animals and humans. We hypothesized that physiological changes in estrogen levels infl uence circulating PCSK9, thereby contributing to the known wide inter-individual variation in its plasma levels, as well as to the established increase in LDL cholesterol (LDL-C) with normal aging. Circulating PCSK9, estradiol, and other metabolic factors were determined in fasting samples from 206 female and 189 male healthy volunteers (age 20-85 years), The mean levels of PCSK9 were 10% higher in females than in males ( P < 0.05). PCSK9 levels were 22% higher in postmenopausal than in premenopausal ( P < 0.001) females. Within the group of premenopausal females, circulating PCSK9 correlated inversely to estrogen levels, and PCSK9 was higher (305 ng/ml) in the follicular phase than in the ovulatory (234 ng/ml) or the luteal (252 ng/ml) phases ( P < 0.05). Changes in endogenous estrogen levels during the menstrual cycle likely contribute to the broad interindividual variation in PCSK9 and LDL-C in normal females. PCSK9 levels increase in females after menopause but not in men during this phase in life. This likely contributes to why LDL-C in women increases in this period. -Ghosh, M., C. Gälman, M. Rudling, and B. Angelin. Infl uence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol. J. Lipid Res. © 2015 by the American Society for Biochemistry and Molecular Biology Inc.


PubMed | Metabolism Unit, Karolinska Institutet, Uppsala University and Lund University
Type: Journal Article | Journal: The American journal of clinical nutrition | Year: 2015

Butter is rich in saturated fat [saturated fatty acids (SFAs)] and can increase plasma low density lipoprotein (LDL) cholesterol, which is a major risk factor for cardiovascular disease. However, compared with other dairy foods, butter is low in milk fat globule membrane (MFGM) content, which encloses the fat. We hypothesized that different dairy foods may have distinct effects on plasma lipids because of a varying content of MFGM.We aimed to investigate whether the effects of milk fat on plasma lipids and cardiometabolic risk markers are modulated by the MFGM content.The study was an 8-wk, single-blind, randomized, controlled isocaloric trial with 2 parallel groups including overweight men and women (n = 57 randomly assigned). For the intervention, subjects consumed 40 g milk fat/d as either whipping cream (MFGM diet) or butter oil (control diet). Intervention foods were matched for total fat, protein, carbohydrates, and calcium. Subjects were discouraged from consuming any other dairy products during the study. Plasma markers of cholesterol absorption and hepatic cholesterol metabolism were assessed together with global gene-expression analyses in peripheral blood mononuclear cells.As expected, the control diet increased plasma lipids, whereas the MFGM diet did not [total cholesterol (SD): +0.30 0.49 compared with -0.04 0.49 mmol/L, respectively (P = 0.024); LDL cholesterol: +0.36 0.50 compared with +0.04 0.36 mmol/L, respectively (P = 0.024); apolipoprotein B:apolipoprotein A-I ratio: +0.03 0.09 compared with -0.05 0.10 mmol/L, respectively (P = 0.007); and non-HDL cholesterol: +0.24 0.49 compared with -0.14 0.51 mmol/L, respectively (P = 0.013)]. HDL-cholesterol, triglyceride, sitosterol, lathosterol, campesterol, and proprotein convertase subtilisin/kexin type 9 plasma concentrations and fatty acid compositions did not differ between groups. Nineteen genes were differentially regulated between groups, and these genes were mostly correlated with lipid changes.In contrast to milk fat without MFGM, milk fat enclosed by MFGM does not impair the lipoprotein profile. The mechanism is not clear although suppressed gene expression by MFGM correlated inversely with plasma lipids. The food matrix should be considered when evaluating cardiovascular aspects of different dairy foods. This trial was registered at clinicaltrials.gov as NCT01767077.


Lundberg J.,Metabolism Unit | Lundberg J.,Karolinska University Hospital | Rudling M.,Metabolism Unit | Rudling M.,Karolinska University Hospital | And 2 more authors.
Current Opinion in Lipidology | Year: 2013

Purpose of review: The interstitium represents the fluid, proteins, solutes, and extracellular matrix comprising the microenvironment of tissues. We here review attempts to characterize the levels and composition of lipoproteins in human interstitial fluid, and identify potentially important questions for future research. Recent findings: Despite the high relevance of understanding how lipoproteins enter and exit the interstitial compartment, and how they interact with extracellular and cellular molecules, scientific progress in this field has been rather slow. This is partly due to methodological difficulties, both regarding how to obtain representative samples and how to perform appropriate measurements to compare patient cohorts and to evaluate responses to treatment. Predominant techniques include peripheral lymph cannulation and suction blister creation, both of which have inherent advantages and disadvantages. Detailed studies comparing the effects of long-term incubation of serum and lymph lipoproteins are compatible with the view that HDL in interstitial fluid takes up free cholesterol from cells and transfers it into the circulation. Summary: Studies of the concentration, composition, functionality, and turnover of interstitial fluid lipoproteins will be of great future interest for understanding how tissue cholesterol metabolism is regulated, and how different diseases link to increased risk for development of atherosclerosis. © 2013 Wolters Kluwer Health.


Troutt J.S.,Eli Lilly and Company | Rudling M.,Metabolism Unit | Rudling M.,Karolinska University Hospital | Persson L.,Metabolism Unit | And 8 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: Hepcidin-25 reduces iron absorption by binding to the intestinal iron transporter ferroportin and causing its degradation. Currently, little is known about the basal regulation of circulating hepcidin-25. In addition, although erythropoietin administration has been reported to decrease the circulating hepcidin concentration, information is limited regarding how other stimulators of erythropoiesis, such as growth hormone (GH), might alter hepcidin-25 concentrations. METHODS: We used a sensitive and specific hepcidin-25 dual-monoclonal antibody sandwich immunoassay to measure hepcidin-25 in healthy human volunteers at various time points throughout the day and during 3 days of fasting and subsequent refeeding. We also measured hepcidin-25 concentrations in healthy volunteers after GH administration. RESULTS: In healthy individuals, hepcidin-25 concentrations displayed a diurnal variation, with concentrations being lowest in the early morning and steadily increasing throughout the day before declining during the evening hours, a pattern that was not influenced by food intake. Prolonged fasting produced statistically significant increases in hepcidin-25 concentrations. Refeeding reversed this process, and GH administration markedly decreased hepcidin-25 concentrations. CONCLUSIONS: Our results indicate that in humans, hepcidin-25 exhibits diurnal changes that can be altered by prolonged fasting, which increases hepcidin-25 concentrations approximately 3-fold after 3 days of fasting, possibly owing to a suppression of erythropoiesis that may occur during the fasting state to preserve tissue iron concentrations. In contrast, GH administration decreased hepcidin-25 concentrations by approximately 65%, presumably by stimulating erythropoiesis. These results indicate that circulating hepcidin-25 concentrations display much more dynamic and rapid variation than might have been anticipated previously. © 2012 American Association for Clinical Chemistry.

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