The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

Visinoni, Sherley; Khalid, Nurul Fathiah Izzati; Joannides, Christos N.; Shulkes, Arthur; Yim, Mildred; Whitehead, Jonathan P.; Tiganis, Tony; Lamont, Benjamin J.; Favaloro, Jenny M.; Proietto, Joseph; Andrikopoulos, Sofianos; Fam, Barbara C

doi:10.2337/db11-1511

Cited by 46 publications

(41 citation statements)

References 49 publications

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“…Mice were tracked for a further 2 weeks on their respective diets. During the 6th week of feeding, voluntary physical activity (individually housed running wheels, which have been shown to correlate well with infrared photoelectric measurements of spontaneous motor activity (Thorburn et al 2000)), resting energy expenditure (REE) and respiratory quotient (RQ; indirect calorimetry; 10 min interval sampling over 75 min during the resting period (daytime)) were measured (Fam et al 2007, Mangiafico et al 2011, Wong et al 2011, Visinoni et al 2012. At the conclusion, mice were anaesthetised in the non-fasted state (0900 h) (Ahren & Scheurink 1998, Fam et al 2007 with an i.p.…”

Section: Feeding Protocol and Energy Balance Measurementsmentioning

confidence: 99%

“…Hypothalamic dissection and RNA/cDNA preparation Whole hypothalami were dissected, and the sections that contained the arcuate nuclei (ARC) were excised, as previously reported (Steinberg et al 2006, Fam et al 2007, Wong et al 2011, Visinoni et al 2012. Sections that contained the paraventricular nuclei (PVN) were also collected to act as a site-specific control for gene expression.…”

Section: Plasma Hormone Concentrationsmentioning

confidence: 99%

“…Sections that contained the paraventricular nuclei (PVN) were also collected to act as a site-specific control for gene expression. RNA and cDNA were prepared from hypothalamic sections and dissected tissues (Fam et al 2007, Wong et al 2011, Visinoni et al 2012.…”

Section: Plasma Hormone Concentrationsmentioning

confidence: 99%

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Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Fam¹,

Sgambellone²,

Ruan³

et al. 2015

Journal of Endocrinology

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Obesity susceptibility in humans and in rodent strains varies in response to the consumption of high-energy density (HED) diets. However, the exact mechanism(s) involved in this susceptibility remain(s) unresolved. The aim of the present study was to gain greater insight into this susceptibility by using C57BL/6J (B6) mice that were separated into obesity-prone (diet-induced obese (DIO)) and obesity-resistant (diet-induced resistant (DR)) groups following an HED diet for 6 weeks. Physiological, biochemical and gene expression assessments of energy balance were performed in the DIO and DR mice on an HED diet and chow-fed mice. The increased weight gain of the DIO mice as compared to the DR mice was associated with increased energy intake and higher plasma leptin and adiponectin levels but not with reduced physical activity or resting energy expenditure. Hypothalamic Pomc gene expression was elevated, but there were no changes in Npy or Agrp expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group as compared to the DR group. Interestingly, ileum expression of G protein-coupled receptor (Gpr) 40 (Gpr40) was significantly increased, whereas Gpr120, Gpr119, Gpr41, and glucagon-like peptide 1 (Glp1) were reduced. Contrastingly, the lower weight gain of the DR group was associated with elevated adipose tissue leptin and adiponectin gene expression, but there were no differences in plasma hormone or hypothalamic gene expression levels as compared to chow-fed mice. Therefore, the present data demonstrate that susceptibility and resistance to diet-induced weight gain in B6 mice appears to be predominantly driven by peripheral rather than hypothalamic modifications, and changes in gut-specific receptors are a potentially important contributor to this variation. Key Words" diet-induced obesity " high-energy density diet " body weight regulation

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Section: Feeding Protocol and Energy Balance Measurementsmentioning

confidence: 99%

Section: Plasma Hormone Concentrationsmentioning

confidence: 99%

See 1 more Smart Citation

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Fam¹,

Sgambellone²,

Ruan³

et al. 2015

Journal of Endocrinology

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“…During times of glucose demand, F-2,6-P 2 levels are reduced, leading to increased activity of FBPase. An aberrant up-regulation of gluconeogenesis, especially when coupled with decreased uptake and metabolism of glucose from the blood into cells, may lead to type 2 diabetes (Visinoni et al, 2012). Inhibition of the liver isoform of FBPase (hlFBPase; the other isoform being the muscle isoform) is therefore an attractive avenue for disease treatment.…”

Section: Introductionmentioning

confidence: 99%

Quadruple space-group ambiguity owing to rotational and translational noncrystallographic symmetry in human liver fructose-1,6-bisphosphatase

Ruf

Tetaz

Schott

et al. 2016

Acta Cryst Sect D Struct Biol

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Fructose-1,6-bisphosphatase (FBPase) is a key regulator of gluconeogenesis and a potential drug target for type 2 diabetes. FBPase is a homotetramer of 222 symmetry with a major and a minor dimer interface. The dimers connected via the minor interface can rotate with respect to each other, leading to the inactive T-state and active R-state conformations of FBPase. Here, the first crystal structure of human liver FBPase in the R-state conformation is presented, determined at a resolution of 2.2 Å in a tetragonal setting that exhibits an unusual arrangement of noncrystallographic symmetry (NCS) elements. SelfPatterson function analysis and various intensity statistics revealed the presence of pseudo-translation and the absence of twinning. The space group is P4 1 2 1 2, but structure determination was also possible in space groups P4 3 2 1 2, P4 1 22 and P4 3 22. All solutions have the same arrangement of three C 2 -symmetric dimers spaced by 1/3 along an NCS axis parallel to the c axis located at (1/4, 1/4, z), which is therefore invisible in a self-rotation function analysis. The solutions in the four space groups are related to one another and emulate a body-centred lattice. If all NCS elements were crystallographic, the space group would be I4 1 22 with a c axis three times shorter and a single FBPase subunit in the asymmetric unit. I4 1 22 is a minimal, non-isomorphic supergroup of the four primitive tetragonal space groups, explaining the space-group ambiguity for this crystal.

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“…The relative quantification method was used to assess the expression level of the target genes. This analysis uses the 2^(KDDC t ) method, which is based on relative quantification of the KO mice to the control mice as previously published (Kebede et al 2008, Visinoni et al 2008, 2012, Mangiafico et al 2011, Wong et al 2011.…”

Section: Rna Extraction and Real-time Pcrmentioning

confidence: 99%

Normal muscle glucose uptake in mice deficient in muscle GLUT4

Fam

Rose

Sgambellone

et al. 2012

Journal of Endocrinology

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Skeletal muscle insulin resistance is a major characteristic underpinning type 2 diabetes. Impairments in the insulin responsiveness of the glucose transporter, Glut4 (Slc2a4), have been suggested to be a contributing factor to this disturbance. We have produced muscle-specific Glut4 knockout (KO) mice using Cre/LoxP technology on a C57BL6/J background and shown undetectable levels of GLUT4 in both skeletal muscle and heart. Our aim was to determine whether complete deletion of muscle GLUT4 does in fact lead to perturbations in glucose homoeostasis. Glucose tolerance, glucose turnover and 2-deoxyglucose uptake into muscle and fat under basal and insulin-stimulated conditions were assessed in 12-week-old KO and control mice using the oral glucose tolerance test (OGTT) and hyperinsulinaemic/euglycaemic clamp respectively. KO mice weighed w17% less and had significantly heavier hearts compared with control mice. Basally, plasma glucose and plasma insulin were significantly lower in the KO compared with control mice, which conferred normal glucose tolerance. Despite the lack of GLUT4 in the KO mouse muscle, glucose uptake was not impaired in skeletal muscle but was reduced in heart under insulin-stimulated conditions. Neither GLUT1 nor GLUT12 protein levels were altered in the skeletal muscle or heart tissue of our KO mice. High-fat feeding did not alter glucose tolerance in the KO mice but led to elevated plasma insulin levels during the glucose tolerance test. Our study demonstrates that deletion of muscle GLUT4 does not adversely affect glucose disposal and glucose tolerance and that compensation from other transporters may contribute to this unaltered homoeostasis of glucose.

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The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity

Cited by 46 publications

References 49 publications

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Quadruple space-group ambiguity owing to rotational and translational noncrystallographic symmetry in human liver fructose-1,6-bisphosphatase

Normal muscle glucose uptake in mice deficient in muscle GLUT4

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