Potato consumption is not associated with cardiometabolic health outcomes in Framingham Offspring Study adults.

Some consider potatoes to be unhealthy vegetables that may contribute to adverse cardiometabolic health outcomes. We evaluated the association between potato consumption (including fried and non-fried types) and three key cardiometabolic outcomes among middle-aged and older adults in the Framingham Offspring Study. We included 2523 subjects ≥30 years of age with available dietary data from 3-d food records. Cox-proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for hypertension, type 2 diabetes or impaired fasting glucose (T2DM/IFG), and elevated triglycerides, adjusting for anthropometric, demographic and lifestyle factors. In the present study, 36 % of potatoes consumed were baked, 28 % fried, 14 % mashed, 9 % boiled and the rest cooked in other ways. Overall, higher total potato intake (≥4 v. <1 cup-equivalents/week) was not associated with risks of T2DM/IFG (HR 0⋅97, 95 % CI 0⋅81, 1⋅15), hypertension (HR 0⋅95; 95 % CI 0⋅80, 1⋅12) or elevated triglycerides (HR 0⋅99, 95 % CI 0⋅86, 1⋅13). Stratified analyses were used to evaluate effect modification by physical activity levels and red meat consumption, and in those analyses, there were no adverse effects of potato intake. However, when combined with higher levels of physical activity, greater consumption of fried potatoes was associated with a 24 % lower risk (95 % CI 0⋅60, 0⋅96) of T2DM/IFG, and in combination with lower red meat consumption, higher fried potato intake was associated with a 26 % lower risk (95 % CI 0⋅56, 0⋅99) of elevated triglycerides. In this prospective cohort, there was no adverse association between fried or non-fried potato consumption and risks of T2DM/IFG, hypertension or elevated triglycerides.

Higher Intakes of Potassium and Magnesium, but Not Lower Sodium, Reduce Cardiovascular Risk in the Framingham Offspring Study.

We explored the dose-response relations of sodium, potassium, magnesium and calcium with cardiovascular disease (CVD) risk in the Framingham Offspring Study, as well as the combined effects of these minerals. Analyses included 2362 30-64 year-old men and women free of CVD at baseline. Cox proportional-hazards models were used estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for mineral intakes and incident CVD. Cox models with restricted cubic spline functions were used to examine dose-response relations, adjusting for confounding by age, sex, body mass index, dietary fiber intake, and time-varying occurrence of hypertension. Lower sodium intake (<2500 vs. ≥3500 mg/d) was not associated with a lower risk of CVD. In contrast, potassium intake ≥3000 (vs. <2500) mg/d was associated with a 25% lower risk (95% CI: 0.59, 0.95), while magnesium intake ≥320 (vs. <240) mg/d led to a 34% lower risk (95% CI: 0.51, 0.87) of CVD. Calcium intake ≥700 (vs. <500) mg/d was associated with a non-statistically significant 19% lower risk. Restricted cubic spline curves showed inverse dose-response relations of potassium and magnesium with CVD risk, but no such associations were observed for sodium or calcium. These results highlight the importance of potassium and magnesium to cardiovascular health.

Animal protein intake reduces risk of functional impairment and strength loss in older adults.

BACKGROUND & AIMS: Protein intake has been shown to lower risk of aging-related functional decline. The goal of this study was to assess long-term effects of weight-adjusted animal (AP) and plant protein (PP) intakes on aging-related change in functional status and grip strength. METHODS: Framingham Offspring Study participants (n = 1896, 891 men and 1005 women), ≥age 50, were followed for an average of 14.4 years. Protein intake derived from two sets of 3-day diet records (exams 3 and 5) was expressed as both weight-adjusted intake (from residuals) and per kilogram of body weight (g/kg/d). Seven tasks from two standardized assessments (Nagi and the Rosow-Breslau scales) were selected to determine functional status at exams 5-9. Functional impairment was defined as failure to complete (or having a lot of difficulty completing) a given task. Grip strength was assessed by dynamometer at exams 7-9. RESULTS: Participants with higher (vs. lower) weight-adjusted intakes of AP and PP maintained higher functional scores (p = 0.001 and p < 0.001, respectively). After accounting for baseline skeletal muscle mass (SMM) and physical activity, only AP was linked with lower risks of functional impairment. Higher AP intake among sedentary individuals led to 29% (95% CI: 0.51-1.00) reduced risks of impairment; among subjects with lower SMM, higher AP was associated with 30% (95% CI: 0.49-0.98) reduced risks. Physical activity and SMM were independently associated with reduced risks of functional impairment, regardless of protein intake. Finally, higher AP intake led to 34% and 48% greater preservation of grip strength in men (p = 0.012) and women (p = 0.034). Results were similar for protein intake expressed as g/kg/d. CONCLUSIONS: Higher AP intake and higher levels of physical activity and SMM were independently associated with lower risks of functional impairment and greater preservation of grip strength in adults over the age of 50 years.

Impaired Glucocorticoid Suppression of TGFß Signaling in Human Omental Adipose Tissues Limits Adipogenesis and May Promote Fibrosis.

Visceral obesity is associated with insulin resistance and higher risk of type 2 diabetes and metabolic diseases. A limited ability of adipose tissues to remodel through the recruitment and differentiation of adipose stem cells (ASCs) is associated with adipose tissue inflammation and fibrosis and the metabolic syndrome. We show that the lower adipogenesis of omental (Om) compared with abdominal subcutaneous (Abdsc) ASCs was associated with greater secretion of TGFß ligands that acted in an autocrine/paracrine loop to activate SMAD2 and suppress adipogenesis. Inhibition of TGFß signaling rescued Om ASC differentiation. In Abdsc ASCs, low concentrations of dexamethasone suppressed TGFß signaling and enhanced adipogenesis, at least in part by increasing TGFBR3 protein that can sequester TGFß ligands. Om ASCs were resistant to these dexamethasone effects; recombinant TGFBR3 increased their differentiation. Pericellular fibrosis, a hallmark of dysfunctional adipose tissue, was greater in Om and correlated with higher level of tissue TGFß signaling activity and lower ASC differentiation. We conclude that glucocorticoids restrain cell-autonomous TGFß signaling in ASCs to facilitate adipogenesis and healthy remodeling in Abdsc and these processes are impaired in Om. Therapies directed at overcoming glucocorticoid resistance in visceral adipose tissue may improve remodeling and help prevent metabolic complications of visceral obesity.

Depot Dependent Effects of Dexamethasone on Gene Expression in Human Omental and Abdominal Subcutaneous Adipose Tissues from Obese Women.

Glucocorticoids promote fat accumulation in visceral compared to subcutaneous depots, but the molecular mechanisms involved remain poorly understood. To identify long-term changes in gene expression that are differentially sensitive or responsive to glucocorticoids in these depots, paired samples of human omental (Om) and abdominal subcutaneous (Abdsc) adipose tissues obtained from obese women during elective surgery were cultured with the glucocorticoid receptor agonist dexamethasone (Dex, 0, 1, 10, 25 and 1000 nM) for 7 days. Dex regulated 32% of the 19,741 genes on the array, while 53% differed by Depot and 2.5% exhibited a Depot*Dex concentration interaction. Gene set enrichment analysis showed Dex regulation of the expected metabolic and inflammatory pathways in both depots. Cluster analysis of the 460 transcripts that exhibited an interaction of Depot and Dex concentration revealed sets of mRNAs for which the responses to Dex differed in magnitude, sensitivity or direction between the two depots as well as mRNAs that responded to Dex only in one depot. These transcripts were also clearly depot different in fresh adipose tissue and are implicated in processes that could affect adipose tissue distribution or functions (e.g. adipogenesis, triacylglycerol synthesis and storage, insulin action). Elucidation of the mechanisms underlying the depot differences in the effect of Dex on the expression of specific genes and pathways that regulate adipose function may offer novel insights into understanding the biology of visceral adipose tissues and their links to metabolic health.

Fat-specific protein 27 inhibits lipolysis by facilitating the inhibitory effect of transcription factor Egr1 on transcription of adipose triglyceride lipase.

Lipolysis in fat tissue represents a major source of circulating fatty acids. Previously, we have found that lipolysis in adipocytes is controlled by early growth response transcription factor Egr1 that directly inhibits transcription of adipose triglyceride lipase, ATGL (Chakrabarti, P., Kim, J. Y., Singh, M., Shin, Y. K., Kim, J., Kumbrink, J., Wu, Y., Lee, M. J., Kirsch, K. H., Fried, S. K., and Kandror, K. V. (2013) Mol. Cell. Biol. 33, 3659-3666). Here we demonstrate that knockdown of the lipid droplet protein FSP27 (a.k.a. CIDEC) in human adipocytes increases expression of ATGL at the level of transcription, whereas overexpression of FSP27 has the opposite effect. FSP27 suppresses the activity of the ATGL promoter in vitro, and the proximal Egr1 binding site is responsible for this effect. FSP27 co-immunoprecipitates with Egr1 and increases its association with and inhibition of the ATGL promoter. Knockdown of Egr1 attenuates the inhibitory effect of FSP27. These results provide a new model of transcriptional regulation of ATGL.

Prolonged efficiency of siRNA-mediated gene silencing in primary cultures of human preadipocytes and adipocytes.

OBJECTIVE: Primary human preadipocytes and differentiated adipocytes in culture are valuable cell culture systems to study adipogenesis and adipose function in relation to human adipose biology. To use these systems for mechanistic studies, siRNA-mediated knockdown of genes for its effectiveness was studied. METHODS: Methods were developed to effectively deliver siRNA for gene silencing in primary preadipocytes isolated from human subcutaneous adipose tissue and newly differentiated adipocytes. Expression level of genes and proteins was measured using quantitative RT-PCR and western blotting. Lipid droplet morphology was observed using microscopy, and glycerol release was quantified as a measure of lipolysis. RESULTS: siRNA-mediated knockdown of genes in primary human preadipocytes resulted in prolonged silencing effects, suppressing genes throughout the process of their differentiation. In newly differentiated adipocytes, siRNA-mediated gene knockdown allowed proteins to stay depleted for at least 5 days. It was possible to re-express a protein after its siRNA-mediated depletion. Importantly, siRNA transfected human adipocytes remained metabolically active, responding to ß-adrenergic stimulation to increase lipolysis. CONCLUSIONS: Our study describes the methods of gene silencing in primary cultures of human preadipocytes and adipocytes and their prolonged effectiveness.

Altered hepatic lipid metabolism contributes to nonalcoholic fatty liver disease in leptin-deficient Ob/Ob mice.

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to obesity, insulin resistance, and abnormal hepatic lipid metabolism; however, the precise regulation of these processes remains poorly understood. Here we examined genes and proteins involved in hepatic oxidation and lipogenesis in 14-week-old leptin-deficient Ob/Ob mice, a commonly studied model of obesity and hepatic steatosis. Obese Ob/Ob mice had increased fasting glucose, insulin, and calculated HOMA-IR as compared with lean wild-type (WT) mice. Ob/Ob mice also had greater liver weights, hepatic triglyceride (TG) content, and markers of de novo lipogenesis, including increased hepatic gene expression and protein content of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1), as well as elevated gene expression of PPARγ and SREBP-1c compared with WT mice. While hepatic mRNA levels for PGC-1α, PPARα, and TFAM were elevated in Ob/Ob mice, measures of mitochondrial function (ß-HAD activity and complete (to CO(2)) and total mitochondrial palmitate oxidation) and mitochondrial OXPHOS protein subunits I, III, and V content were significantly reduced compared with WT animals. In summary, reduced hepatic mitochondrial content and function and an upregulation in de novo lipogenesis contribute to obesity-associated NAFLD in the leptin-deficient Ob/Ob mouse.

Sterculic Oil, a Natural SCD1 Inhibitor, Improves Glucose Tolerance in Obese ob/ob Mice.

Obesity and its metabolic complications are associated with increased expression/activity of stearoyl-CoA desaturase-1 (SCD1), a major regulator of lipid metabolism. Reduction or ablation of this enzyme is associated with an improved metabolic profile and has gained attention as a target for pharmaceutical development. Sterculic oil (SO) is a known inhibitor of SCD1 and may provide a natural approach for treating obesity and/or insulin resistance. The purpose of this study was to evaluate the effects of SO consumption in leptin-deficient ob/ob mice, a model of obesity and insulin resistance. Five-week-old male mice received either an AIN-93G (control) or an AIN-93G diet containing 0.5% SO. After 9 weeks, SO supplementation did not alter food intake or body weight; however, the desaturase indices, a proxy of SCD1 activity, were reduced in liver and adipose tissue of SO-supplemented animals. This reduction was associated with improved glucose and insulin tolerance and attenuated hepatic inflammation in obese ob/ob mice, while no appreciable changes were observed in lean control mice receiving SO. Future studies are needed to better understand the mechanism(s) by which SO is functioning to improve glucose metabolism and to further explore the nutraceutical potential and health implications of SO supplementation.

A comparison of inflammatory and oxidative stress markers in adipose tissue from weight-matched obese male and female mice.

Expansion of intra-abdominal adipose tissue and the accompanying inflammatory response has been put forward as a unifying link between obesity and the development of chronic diseases. However, an apparent sexual dimorphism exists between obesity and chronic disease risk due to differences in the distribution and abundance of adipose tissue. A range of experimental protocols have been employed to demonstrate the role of estrogen in regulating health benefits; however, most studies are confounded by significant differences in body weight and adiposity. Therefore, the purpose of this study was to compare weight-matched obese male and female mice to determine if the sex-dependent health benefits remain when body weight is similar. The development of obesity in female mice receiving a high-fat diet was delayed; however, subsequent comparisons of weight-matched obese mice revealed greater adiposity in obese female mice. Despite excess adiposity and enlarged adipocyte size, obese females remained more glucose tolerant than weight-matched male mice, and this benefit was associated with increased expression of adiponectin and reductions in immune cell infiltration and oxidative stress in adipose tissue. Therefore, the protective benefits of estrogen persist in the obese state and appear to improve the metabolic phenotype of adipose tissue and the individual.