Association of pre-diagnostic physical exercise and peri-diagnostic body composition with mortality in non-metastatic colorectal cancer.

PURPOSE: Sarcopenia and myosteatosis, quantified via computed tomography (CT), are associated with poor colorectal cancer outcomes. These body composition estimates can be influenced by physical exercise. We explored the correlation between pre-diagnostic physical exercise, body composition close to diagnosis, and the combined prognosis impact of these factors. METHODS: We studied 519 stage I-III colorectal cancer (CRC) cases diagnosed 2000-2016 with pre-diagnostic self-reported recreational physical exercise data collected in the prospective, population-based Northern Sweden Health and Disease Study, and CT-estimated skeletal muscle index (SMI) or skeletal muscle density (SMD). Risk estimates were calculated by multivariable logistic regression and Cox proportional hazards models. RESULTS: No association was seen between low pre-diagnostic physical exercise and sarcopenia/myosteatosis in the multivariable model adjusted for age, sex, educational level, tumor stage, and tumor location. In multivariable Cox regression models, the combination of low pre-diagnostic physical exercise and either sarcopenia or myosteatosis at the time of diagnosis was associated with cancer-specific mortality compared to the reference group of high physical exercise combined with no sarcopenia/myosteatosis (adjusted HR 1.94 95% CI 1.00-3.76 for sarcopenia and adjusted HR 2.39 95% CI 1.16-4.94 for myosteatosis). CONCLUSIONS: The combined presence of low pre-diagnostic physical exercise and sarcopenia or myosteatosis was associated with increased CRC-specific mortality. Despite the positive effect on prognosis, physical exercise did not alter body composition estimates at diagnosis, which could indicate attenuation from other factors.

Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice.

Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wild-type mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4.

Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.

Differences in metabolic profiles between the Burmese, the Maine coon and the Birman cat-Three breeds with varying risk for diabetes mellitus.

Feline diabetes mellitus shares many features with type 2 diabetes in people, regarding clinical presentation, physiology, and pathology. A breed predisposition for type 2 diabetes has been identified, with the Burmese breed at a fivefold increased risk of developing the condition compared to other purebred cats. We aimed to characterize the serum metabolome in cats (n = 63) using nuclear magnetic resonance metabolomics, and to compare the metabolite pattern of Burmese cats with that of two cat breeds of medium or low risk of diabetes, the Maine coon (MCO) and Birman cat, respectively. Serum concentrations of adiponectin, insulin and insulin-like growth factor-1 were also measured (n = 94). Burmese cats had higher insulin and lower adiponectin concentrations than MCO cats. Twenty one metabolites were discriminative between breeds using a multivariate statistical approach and 15 remained significant after adjustment for body weight and body condition score. Burmese cats had higher plasma levels of 2-hydroxybutyrate relative to MCO and Birman cats and increased concentrations of 2-oxoisocaproic acid, and tyrosine, and lower concentrations of dimethylglycine relative to MCO cats. The metabolic profile of MCO cats was characterized by high concentrations of arginine, asparagine, methionine, succinic acid and low levels of acetylcarnitine while Birman cats had the highest creatinine and the lowest taurine plasma levels, compared with MCO and Burmese. The pattern of metabolites in Burmese cats is similar to that in people with insulin resistance. In conclusion, the metabolic profile differed between healthy cats of three breeds. Detection of an abnormal metabolome might identify cats at risk of developing diabetes.

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice.

BACKGROUND: Excess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice. METHODS: Female C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR. RESULTS: The increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state. CONCLUSIONS: Pair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.

Elevated leukocyte count and adverse hospital events in patients with acute coronary syndromes: findings from the Global Registry of Acute Coronary Events (GRACE).

OBJECTIVE: To examine the association between elevated leukocyte count and hospital mortality and heart failure in patients enrolled in the multinational, observational Global Registry of Acute Coronary Events (GRACE). BACKGROUND: Elevated leukocyte count is associated with adverse hospital outcomes in patients presenting with acute myocardial infarction (AMI). The association of this prognostic factor with hospital mortality and heart failure in patients with other acute coronary syndromes (ACS) is unclear. METHODS: We examined the association between admission leukocyte count and hospital mortality and heart failure in 8269 patients presenting with an ACS. This association was examined separately in patients with ST-segment elevation AMI, non-ST-segment elevation AMI, and unstable angina. Leukocyte count was divided into 4 mutually exclusive groups (Q): Q1 <6000, Q2 = 6000-9999, Q3 = 10,000-11,999, Q4 >12,000. Multiple logistic regression analysis was performed to examine the association between elevated leukocyte count and hospital events while accounting for the simultaneous effect of several potentially confounding variables. RESULTS: Increasing leukocyte count was significantly associated with hospital death (adjusted odds ratio [OR] 2.8, 95% CI 2.1-3.6 for Q4 compared to Q2 [normal range]) and heart failure (OR 2.7, 95% CI 2.2-3.4) for patients presenting with ACS. This association was seen in patients with ST-segment elevation AMI (OR for hospital death 3.2, 95% CI 2.1-4.7; OR for heart failure 2.4, 95% CI 1.8-3.3), non-ST-segment elevation AMI (OR for hospital death 1.9, 95% CI 1.2-3.0; OR for heart failure 1.7, 95% CI 1.1-2.5), or unstable angina (OR for hospital death 2.8, 95% CI 1.4-5.5; OR for heart failure 2.0, 95% CI 0.9-4.4). CONCLUSION: In men and women of all ages with the spectrum of ACS, initial leukocyte count is an independent predictor of hospital death and the development of heart failure.