Caspase-2 deficiency enhances whole-body carbohydrate utilisation and prevents high-fat diet-induced obesity

Published online 26 October 2017Caspase-2 has been shown to be involved in metabolic homeostasis. Here, we show that caspase-2 deficiency alters basal energy metabolism by shifting the balance in fuel choice from fatty acid to carbohydrate usage. At 4 weeks of age, whole-body carbohydrate utilisation was increased in Casp2-/- mice and was maintained into adulthood. By 17 weeks of age, Casp2-/- mice had reduced white adipose mass, smaller white adipocytes decreased fasting blood glucose and plasma triglycerides but maintained normal insulin levels. When placed on a 12-week high-fat diet (HFD), Casp2-/- mice resisted the development of obesity, fatty liver, hyperinsulinemia and insulin resistance. In addition, HFD-fed Casp2-/- mice had reduced white adipocyte hypertrophy, apoptosis and expansion of both subcutaneous and visceral adipose depots. Increased expression of UCP1 and the maintenance of adiponectin levels in white adipose tissue of HFD-fed Casp2-/- mice indicated increased browning and adipocyte hyperplasia. We found that while the preference for whole-body carbohydrate utilisation was maintained, HFD-fed Casp2-/- mice were not impaired in their ability to switch to utilising fats as a fuel source. Our findings suggest that caspase-2 impacts basal energy metabolism by regulating adipocyte biology and fat expansion, most likely via a non-apoptotic function. Furthermore, we show that caspase-2 deficiency shifts the balance in fuel choice towards increased carbohydrate utilisation and propose that this is due to mild energy stress. As a consequence, Casp2-/- mice show an adaptive remodelling of adipose tissue that protects from HFD-induced obesity and improves glucose homeostasis while paradoxically increasing their susceptibility to oxidative stress induced damage and premature ageing.Claire H Wilson, Andrej Nikolic, Stephen J Kentish, Marianne Keller, George Hatzinikolas, Loretta Dorstyn, Amanda J Page and Sharad Kuma

The effects of a whey protein and guar gum-containing preload on gastric emptying, glycaemia, small intestinal absorption and blood pressure in healthy older subjects

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.publishedVersio

Time-restricted feeding prevents ablation of diurnal rhythms in gastric vagal afferent mechanosensitivity observed in high-fat diet-induced obese mice

Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food related stimuli allowing time of day specific satiety signalling. This diurnal rhythmicity is ablated in high fat diet (HFD)-induced obesity. Time restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF.Eight-week old male C57BL/6 mice (N=256) were fed a standard laboratory diet (SLD) or HFD for 12wks. After 4wks diet acclimatisation the mice were fed either ad libitum or only during the light (zeitgeber (ZT)0-12) or dark phase (ZT12-24) for 8wks. A subgroup of mice from all conditions (N=8/condition) were placed in metabolic cages. After 12wks, ex vivo GVA recordings were taken at 3h intervals starting at ZT0.HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice but decreased weight gain in the HFD mice irrespective of the TRF period. In SLD mice diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity was dampened. Loss of diurnal rhythmicity in HFD-mice was abrogated by TRF.In conclusion, diurnal rhythmicity in GVA responses to food related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.SIGNIFICANCE STATEMENTDiurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behaviour, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high fat diet-induced (HFD) obese mice and more importantly prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.Stephen J. Kentish, George Hatzinikolas, Hui Li, Claudine L. Frisby, Gary A. Wittert and Amanda J. Pag

Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice

Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2 (-/-) ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 (-/-) mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18-22 months) male Casp2 (-/-) mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 (-/-) mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 (-/-) mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 (-/-) mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.CH Wilson, A Nikolic, SJ Kentish, S Shalini, G Hatzinikolas, AJ Page, L Dorstyn and S Kuma

Effects of substitution, and adding of carbohydrate and fat to whey-protein on energy intake, appetite, gastric emptying, glucose, insulin, ghrelin, cck and glp-1 in healthy older men - a randomized controlled trial

Protein-rich supplements are used widely for the management of malnutrition in the elderly. We reported previously that the suppression of energy intake by whey protein is less in older than younger adults. The aim was to determine the effects of substitution, and adding of carbohydrate and fat to whey protein, on ad libitum energy intake from a buffet meal (180-210 min), gastric emptying (3D-ultrasonography), plasma gut hormone concentrations (0-180 min) and appetite (visual analogue scales), in healthy older men. In a randomized, double-blind order, 13 older men (75 ± 2 years) ingested drinks (~450 mL) containing: (i) 70 g whey protein (280 kcal; 'P₂₈₀'); (ii) 14 g protein, 28 g carbohydrate, 12.4 g fat (280 kcal; 'M₂₈₀'); (iii) 70 g protein, 28 g carbohydrate, 12.4 g fat (504 kcal; 'M₅₀₄'); or (iv) control (~2 kcal). The caloric drinks, compared to a control, did not suppress appetite or energy intake; there was an increase in total energy intake (drink + meal, p < 0.05), which was increased most by the M₅₀₄-drink. P₂₈₀- and M₅₀₄-drink ingestion were associated with slower a gastric-emptying time (n = 9), lower ghrelin, and higher cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) than M₂₈₀ (p < 0.05). Glucose and insulin were increased most by the mixed-macronutrient drinks (p < 0.05). In conclusion, energy intake was not suppressed, compared to a control, and particularly whey protein, affected gastric emptying and gut hormone responses.Caroline Giezenaar, Yonta van der Burgh, Kylie Lange, Seva Hatzinikolas, Trygve Hausken, Karen L. Jones, Michael Horowitz, Ian Chapman, and Stijn Soene

Acute Administration of the GLP-1 Receptor Agonist Lixisenatide Diminishes Postprandial Insulin Secretion in Healthy Subjects But Not in Type 2 Diabetes, Associated with Slowing of Gastric Emptying

Published online 22 April 2022Introduction: It is uncertain whether lixisenatide has postprandial insulinotropic effects when its effect on slowing gastric emptying is considered, in healthy subjects and type 2 diabetes mellitus (T2DM). We evaluated the effects of single administration of 10 lg sc lixisenatide on glycaemia, insulin secretion and gastric emptying (GE), measured using the ‘gold standard’ technique of scintigraphy following an oral glucose load (75 g glucose). Methods: Fifteen healthy subjects (nine men, six women; age 67.2 ± 2.3 years) and 15 patients with T2DM (nine men, six women; age 61.9 ± 2.3 years) had measurements of GE, plasma glucose, insulin and C-peptide for 180 min after a radiolabeled 75 g glucose drink on two separate days. All subjects received lixisenatide (10 lg sc) or placebo in a randomised, double-blind, crossover fashion 30 min before the drink. Insulin secretory response (ISR) was determined using the C-peptide deconvolution method. Results: GE was markedly slowed by lixisenatide compared with placebo in both healthy subjects (1.45 ± 0.10 kcal/min for placebo vs. 0.60 ± 0.14 kcal/min for lixisenatide) and diabetes (1.57 ± 0.06 kcal/min for placebo vs. 0.75 ± 0.13 kcal/min for lixisenatide) (both P\0.001) with no difference between the two groups (P = 0.42). There was a moderate to strong inverse correlation between the early insulin secretory response calculated at 60 min and gastric retention at 60 min with lixisenatide treatment in healthy subjects (r = - 0.8, P = 0.0003) and a trend in type 2 diabetes (r = - 0.4, P = NS), compared with no relationships in the placebo arms (r = - 0.02, P = NS, healthy subjects) and (r = - 0.16, P = NS, type 2 diabetes). Conclusion: The marked slowing of GE of glucose induced by lixisenatide is associated with attenuation in the rise of postprandial glucose in both healthy subjects and diabetes and early insulin secretory response in healthy subjects.Chinmay S. Marathe . Hung Pham . Tongzhi Wu . Laurence G. Trahair . Rachael S. Rigda . Madeline D. M. Buttfield . Seva Hatzinikolas . Kylie Lange . Christopher K. Rayner . Andrea Mari . Michael Horowitz . Karen L. Jone

Drilled-in inserts in masonry construction

Structural engineering report SER 111 | SER-ID SER11