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In addition to controlling blood pressure, cardiac natriuretic peptides (NPs) can stimulate lipolysis in adipocytes and promote the "browning" of white adipose tissue. NPs may also increase the oxidative capacity of skeletal muscle. To unravel the contribution of NP-stimulated metabolism in adipose tissue compared to that in muscle in vivo, we generated mice with tissue-specific deletion of the NP clearance receptor, NPRC, in adipose tissue ( ) or in skeletal muscle ( ). We showed that, similar to null mice, mice, but not mice, were resistant to obesity induced by a high-fat diet. mice exhibited increased energy expenditure, improved insulin sensitivity, and increased glucose uptake into brown fat. These mice were also protected from diet-induced hepatic steatosis and visceral fat inflammation. These findings support the conclusion that NPRC in adipose tissue is a critical regulator of energy metabolism and suggest that inhibiting this receptor may be an important avenue to explore for combating metabolic disease.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Purpose Dietary fat may play a role in lung carcinogenesis. Findings from epidemiologic studies, however, remain inconsistent. In this pooled analysis of 10 prospective cohort studies from the United States, Europe, and Asia, we evaluated the associations of total and specific types of dietary fat with lung cancer risk. Methods Cox regression was used to estimate hazard ratios (HRs) and 95% CIs in each cohort. Study-specific risk estimates were pooled by random- or fixed-effects meta-analysis. The first 2 years of follow-up were excluded to address potential influence of preclinical dietary changes. Results Among 1,445,850 participants, 18,822 incident cases were identified (mean follow-up, 9.4 years). High intakes of total and saturated fat were associated with an increased risk of lung cancer (for highest v lowest quintile: HR, 1.07 and 1.14, respectively; 95% CI, 1.00 to 1.15 and 1.07 to 1.22, respectively; P for trend for both < .001). The positive association of saturated fat was more evident among current smokers (HR, 1.23; 95% CI, 1.13 to 1.35; P for trend < .001) than former/never smokers ( P for interaction = .004), and for squamous cell and small cell carcinoma (HR, 1.61 and 1.40, respectively; 95% CI, 1.38 to 1.88 and 1.17 to 1.67, respectively; P for trend for both < .001) than other histologic types ( P for heterogeneity < .001). In contrast, a high intake of polyunsaturated fat was associated with a decreased risk of lung cancer (HR, 0.92; 95% CI, 0.87 to 0.98 for highest v lowest quintile; P for trend = .02). A 5% energy substitution of saturated fat with polyunsaturated fat was associated with a 16% to 17% lower risk of small cell and squamous cell carcinoma. No associations were found for monounsaturated fat. Conclusion Findings from this large, international cohort consortium suggest that modifying dietary fat intake (ie, replacing saturated fat with polyunsaturated fat) may reduce lung cancer risk, particularly among smokers and for squamous cell and small cell carcinoma.
BACKGROUND - Whether polyunsaturated fatty acids (PUFA) are associated with end-stage renal disease (ESRD) in populations with a high burden of risk factors for kidney disease is unknown. We sought to determine whether PUFA intake is associated with ESRD.
METHODS - We conducted a nested case-control study of ESRD within the Southern Community Cohort Study (SCCS), a prospective cohort of low-income blacks and whites in the southeastern US (2002-2009). Through 2012, 1,074 incident ESRD cases were identified by linkage with the United States Renal Data System and matched to 3,230 controls by age, sex and race. Dietary intake of total, n-3 or n-6 PUFA was assessed from a validated food frequency questionnaire administered at baseline. Odds ratios (ORs) and 95 % confidence intervals (CIs) were computed from logistic regression models that included matching variables, body mass index, smoking, diabetes, hypertension, education, income, total energy intake and percent energy from protein and saturated fat.
RESULTS - The mean (SD) age of participants was 55 (9) years. Most participants were women (55 %), black (87 %), with hypertension (67 %) and on average obtained 8 % of their energy from PUFA. Higher PUFA intake was marginally associated with a lower risk of ESRD in adjusted analyses. The adjusted odds ratios (95 % confidence intervals) for ESRD for the 5 vs. 1 quintile of PUFA were 0.79 (0.60-1.05; P = 0.06) for total PUFA, 0.81 (0.61-1.06; P = 0.04) for n-6 PUFA and 0.93 (0.71-1.21; P = 0.45) for n-3 PUFA.
CONCLUSIONS - We observed a marginally significant inverse trend between dietary PUFA intake and ESRD incidence, mainly driven by n-6 fatty acid intake. Our findings require replication but suggest that a diet rich in n-6 PUFA may prevent ESRD development in a population with a high burden of kidney disease risk factors.
BACKGROUND - Previous studies have suggested that for clinical purposes, subjects with fasting triglycerides (TGs) between 89-180 mg/dl (1-2 mmol/l) would benefit from postprandial TGs testing.
OBJECTIVE - To determine the postprandial TG response in 2 independent studies and validate who should benefit diagnostically from an oral-fat tolerance test (OFTT) in clinical practice.
METHODS - A population of 1002 patients with coronary heart disease (CHD) from the CORDIOPREV clinical trial and 1115 white US subjects from the GOLDN study underwent OFTTs. Subjects were classified into 3 groups according to fasting cut points of TGs to predict the usefulness of OFTT: (1) TG < 89 mg/dl (<1 mmol/l); (2) TG, 89-180 mg/dl (1-2 mmol/l); and (3) TG > 180 mg/dl (>2 mmol/l). Postprandial TG concentration at any point > 220 mg/dl (>2.5 mmol/l) has been pre-established as an undesirable postprandial response.
RESULTS - Of the total, 49% patients with CHD and 42% from the general population showed an undesirable response after the OFTT. The prevalence of undesirable postprandial TG in the CORDIOPREV clinical trial was 12.8, 50.3, and 89.7%, in group 1, 2, and 3, respectively (P < .001) and 11.2, 58.1, and 97.5% in group 1, 2, and 3, respectively (P < .001) in the GOLDN study.
CONCLUSIONS - These two studies validate the predictive values reported in a previous consensus. Moreover, the findings of the CORDIOPREV and GOLDN studies show that an OFTT is useful to identify postprandial hyperlipidemia in subjects with fasting TG between 1-2 mmol/l (89-180 mg/dL), because approximately half of them have hidden postprandial hyperlipidemia, which may influence treatment. An OFTT does not provide additional information regarding postprandial hyperlipidemia in subjects with low TG (<1 mmol/l, <89 mg/dL) or increased TG (>2 mmol/l, >180 mg/dl).
Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.
BACKGROUND & AIMS - The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process.
METHODS - Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6-8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6-8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters.
RESULTS - Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) (P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls (P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid (P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV (P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended.
CONCLUSIONS - The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS.
Copyright © 2016 Elsevier Inc. All rights reserved.
In mammals a network of circadian clocks coordinates behavior and physiology with 24-h environmental cycles. Consumption of high-fat diet disrupts this temporal coordination by advancing the phase of the liver molecular clock and altering daily rhythms of eating behavior and locomotor activity. In this study we sought to determine whether these effects of high-fat diet on circadian rhythms were reversible. We chronically fed mice high-fat diet and then returned them to low-fat chow diet. We found that the phase of the liver PERIOD2::LUCIFERASE rhythm was advanced (by 4h) and the daily rhythms of eating behavior and locomotor activity were altered for the duration of chronic high-fat diet feeding. Upon diet reversal, the eating behavior rhythm was rapidly reversed (within 2 days) and the phase of the liver clock was restored by 7 days of diet reversal. In contrast, the daily pattern of locomotor activity was not restored even after 2 weeks of diet reversal. Thus, while the circadian system is sensitive to changes in the macronutrient composition of food, the eating behavior rhythm and liver circadian clock are specifically tuned to respond to changes in diet.
The main purpose of this study was to examine whether the Supplemental Nutrition Program for Women, Infants and Children (WIC) helped mothers of overweight/obese preschool children to cut down on dietary fat and sugar intake for their families. Data from the Children Eating Well for Health (CHEW) Nutrition Survey, a probability sample of 150 (50 each White, Black and Hispanic) families with preschoolers participating in the WIC program in Nashville/Davidson County, Tennessee, were analyzed using logistic regression modeling. Mothers who reported that the WIC program helped them reduce fat intake were 2.5 times more likely to have an overweight/obese child and 2.1 times more likely to be obese themselves. No significant effects were found for adding sugar. These results suggest that the mothers in this sample were applying WIC nutritional counseling to use food preparation techniques that cut down on added fats for themselves and their children who were at risk due to weight status.
The adenosine triphosphate-binding cassette (ABC) transporter G5/G8 is critical in protecting the body from accumulating dietary plant sterols. Expressed in the liver and small intestine, it transports plant sterols into the biliary and intestinal lumens, thus promoting their excretion. The extent to which G5/G8 regulates cholesterol absorption remains unclear. G5/G8 is also implicated in reducing the absorption of dietary triacylglycerols (TAG) by unknown mechanisms. We hypothesized that G5/G8 suppresses the production of chylomicrons, and its deficiency would enhance the absorption of both dietary TAG and cholesterol. The aim of this study was to investigate the effects of G5/G8 deficiency on lipid uptake and secretion into the lymph under steady-state conditions. Surprisingly, compared with wild-type mice (WT) (n = 9), G5/G8 KO (n = 13) lymph fistula mice given a continuous intraduodenal infusion of [3H]-TAG and [14C]-cholesterol showed a significant (P < 0.05) reduction in lymphatic transport of both [(3)H]-TAG and [(14)C]-cholesterol, concomitant with a significant (P < 0.05) increase of [(3)H]-TAG and [(14)C]-cholesterol accumulated in the intestinal lumen. There was no difference in the total amount of radiolabeled lipids retained in the intestinal mucosa between the two groups. G5/G8 KO mice given a bolus of TAG showed reduced intestinal TAG secretion compared with WT, suggesting an independent role for G5/G8 in facilitating intestinal TAG transport. Our data demonstrate that G5/G8 deficiency reduces the uptake and secretion of both dietary TAG and cholesterol by the intestine, suggesting a novel role for the sterol transporter in the formation and secretion of chylomicrons.
Both short- (1 wk) and long-term (2-12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.