High-fat High-calorie Diet Research Articles

Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan.

Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.

Young, healthy males and females present cardiometabolic protection against the detrimental effects of a 7-day high-fat high-calorie diet

PurposeHigh-fat, high-calorie (HFHC) diets have been used as a model to investigate lipid-induced insulin resistance. Short-term HFHC diets reduce insulin sensitivity in young healthy males, but to date, no study has directly compared males and females to elucidate sex-specific differences in the effects of a HFHC diet on functional metabolic and cardiovascular outcomes.MethodsEleven males (24 ± 4 years; BMI 23 ± 2 kg.m−2; V̇O2 peak 62.3 ± 8.7 ml.min−1.kg−1FFM) were matched to 10 females (25 ± 4 years; BMI 23 ± 2 kg.m−2; V̇O2 peak 58.2 ± 8.2 ml.min−1.kg−1FFM). Insulin sensitivity, measured via oral glucose tolerance test, metabolic flexibility, arterial stiffness, body composition and blood lipids and liver enzymes were measured before and after 7 days of a high-fat (65% energy) high-calorie (+ 50% kcal) diet.ResultsThe HFHC diet did not change measures of insulin sensitivity, metabolic flexibility or arterial stiffness in either sex. There was a trend towards increased total body fat mass (kg) after the HFHC diet (+ 1.8% and + 2.3% for males and females, respectively; P = 0.056). In contrast to females, males had a significant increase in trunk to leg fat mass ratio (+ 5.1%; P = 0.005).ConclusionLean, healthy young males and females appear to be protected from the negative cardio-metabolic effects of a 7-day HFHC diet. Future research should use a prolonged positive energy balance achieved via increased energy intake and reduced energy expenditure to exacerbate negative metabolic and cardiovascular functional outcomes to determine whether sex-specific differences exist under more metabolically challenging conditions.

A 7-day high-fat, high-calorie diet induces fibre-specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle.

We have recently shown that a high-fat, high-calorie (HFHC) diet decreases whole body glucose clearance without impairing skeletal muscle insulin signalling, in healthy lean individuals. These diets are also known to increase skeletal muscle IMTG stores, but the effect on lipid metabolites leading to skeletal muscle insulin resistance has not been investigated. This study measured the effect of 7days' HFHC diet on (1) skeletal muscle concentration of lipid metabolites, and (2) potential changes in the perilipin (PLIN) content of the lipid droplets storing intramuscular triglyceride (IMTG). The HFHC diet increased PLIN3 protein expression and redistributed PLIN2 to lipid droplet stores in type I fibres. The HFHC diet increased IMTG content in type I fibres, while lipid metabolite concentrations remained the same. The data suggest that the increases in IMTG stores assists in reducing the accumulation of lipid metabolites known to contribute to skeletal muscle insulin resistance. A high-fat, high-calorie (HFHC) diet reduces whole body glucose clearance without impairing skeletal muscle insulin signalling in healthy lean individuals. HFHC diets also increase skeletal muscle lipid stores. However, unlike certain lipid metabolites, intramuscular triglyceride (IMTG) stored within lipid droplets (LDs) does not directly contribute to skeletal muscle insulin resistance. Increased expression of perilipin (PLIN) proteins and colocalisation to LDs has been shown to assist in IMTG storage. We aimed to test the hypothesis that 7days on a HFHC diet increases IMTG content while minimising accumulation of lipid metabolites known to disrupt skeletal muscle insulin signalling in sedentary and obese individuals. We also aimed to identify changes in expression and subcellular distribution of proteins involved in IMTG storage. Muscle biopsies were obtained from the m. vastus lateralis of 13 (11 males, 2 females) healthy lean individuals (age: 23±2.5years; body mass index: 24.5±2.4kgm-2 ), following an overnight fast, before and after consuming a high-fat (64% energy), high-calorie (+47% kcal) diet for 7days. After the HFHC diet, IMTG content increased in type I fibres only (+101%; P<0.001), whereas there was no change in the concentration of either total diacylglycerol (P=0.123) or total ceramides (P=0.150). Of the PLINs investigated, only PLIN3 content increased (+50%; P<0.01) solely in type I fibres. LDs labelled with PLIN2 increased (+80%; P<0.01), also in type I fibres only. We propose that these adaptations of LDs support IMTG storage and minimise accumulation of lipid metabolites to protect skeletal muscle insulin signalling following 7days' HFHC diet.

PL-017 High-fat overfeeding increases intramuscular triglyceride content and perilipin protein expression in human skeletal muscle

Objective High-fat high-calorie diets can induce whole body insulin resistance (IR) whilst increasing stores of intramuscular triglyceride (IMTG) contained within lipid droplets (LD). Perilipin (PLIN) proteins assist in IMTG storage. Synaptosomal-associated protein (SNAP23) may support LD growth and also direct IMTG-derived fatty acids (FA) to mitochondria for β-oxidation. The objectives of this study were: 1) to test the hypothesis that 7 days of high-fat overfeeding increases IMTG content to prevent lipid induced muscle IR and 2) identify changes in PLINs, SNAP23 and mitochondria content and colocalisation of PLINs with LD, and SNAP23 with LD and mitochondria.&#x0D; Methods Muscle biopsies were obtained from thevastus lateralisof thirteen healthy individuals (age: 23±1years, BMI: 24.4±0.7kg.m-2) before (0min) and during (30min) an oral glucose tolerance test (OGTT), pre and post 7-days consuming a high-fat (65% energy) high-calorie (+50% kcal) diet. IMTG, PLIN2, PLIN3, PLIN5, SNAP23 and mitochondria content were measured using (semi)-quantitative confocal immunofluorescence microscopy. PLIN2, PLIN3 and PLIN5 colocalisation to LD was measured using object-based colocalisation analyses. Pearson’s correlation coefficient quantified colocalisation between SNAP23 and plasma membrane (PM), mitochondria and LD. Phosphorylation of intermediates of the muscle insulin-signalling cascade (Akt and AS160) were measured at 0 and 30 min of the OGTT before and after the dietary intervention.&#x0D; Results Following overfeeding phosphorylation of Akt and AS160 in muscle was not impaired during the OGTT, however Matsuda index of whole-body insulin sensitivity decreased (-23%; P &lt; 0.01). IMTG content increased in type I fibres (+100%; P &lt; 0.001) due to both an increase in LD number (+43%; P &lt; 0.001) and size (+44%; P&lt; 0.001). Of the PLINs investigated, only PLIN3 content increased (+50%;P &lt; 0.01) exclusively in type I fibres. PLIN2-associated LD increased (+80%; P &lt; 0.01) in type I fibres only, whereas PLIN3 and PLIN5-associated LD were unaltered. SNAP23 and mitochondria content did not change, nor did the colocalisation of SNAP23 with the PM, mitochondria or LD.&#x0D; Conclusions Our data confirm the hypothesis that following high-fat overfeeding IMTG stores increased whilst activation of key muscle insulin signalling components were maintained. The increase in IMTG stores is likely supported by the concurrent increase in total PLIN3 content and a redistribution of existing stores of PLIN2 to the expanded LD pool in type I fibres. To confirm if increased IMTG storage protects muscle from IR future research should determine whether meal-derived FAs are directed to IMTG rather than ceramides and diacylglycerol.

Impact of rural-urban environment on metabolic profile and response to a 5-day high-fat diet

Epidemiological studies have indicated that rural living might be protective against type 2 diabetes development. We compared the metabolic profile and response to a short-term high-fat high-calorie diet (HFD) of men with the same genetic background living in an urban and rural area of Indonesia. First, we recruited 154 Floresian male subjects (18–65 years old), of whom 105 lived in a rural area (Flores) and 49 had migrated and lived in urban area (Jakarta) for more than 1 year. The urban group had significantly higher whole-body insulin resistance (IR), as assessed by homeostatic-model-assessment of IR (HOMA-IR), [mean difference (95% CI), p-value: 0.10 (0.02–0.17), p = 0.01]. Next, we recruited 17 urban and 17 rural age-and-BMI-matched healthy-young-male volunteers for a 5-day HFD challenge. The HOMA-IR increased in both groups similarly −0.77 (−2.03–0.49), p = 0.22]. Neither rural living nor factors associated with rural living, such as current helminth infection or total IgE, were associated with protection against acute induction of IR by HFD.

High fat diet risk factor for gingival Immunosuppression and cancer

ObjectiveHigh fat diet leading to obesity has been associated with many diseases including cancer. We determined the effect of high fat diet and obesity in the phenotype and function of immune cell infiltrates within different tissues including gingival tissues of mice with wild type and targeted KRAS mutations in the pancreas.Experimental methodsConditional LSL‐KRASG12D and p48‐Cre or PDX‐1‐Cre mice were bred and their offsprings were used for the studies. Mice with both the KrasG12D and Cre allele were designated as mutant mice (KC). Mice with neither the KrasG12D nor the Cre allele were used as wildtype (WT). Mice were fed either a high fat, high calorie diet (HFCD) or a control diet (CD) for 4 to 6 months before they were used for experiments. NK cytotoxicity was determined by 51Cr release assay and cytokine secretion by ELISA.ResultsThe Following profiles were obtained for NK cell cytotoxicity and secretion of IFN‐g from NK cells purified from spleen of KC or WT mice fed either with CD or HFCD (WT(CD)&gt;WT(HFCD)&gt;KC(CD)&gt;KC(HFCD). Immune cells from blood and pancreas exhibited similar pattern of cytotoxicity to those obtained from the spleen but inverse profile of IFN‐g and IL‐6 secretion (WT(CD)&lt;WT(HFCD)&lt;KC(CD)&lt;KC(HFCD) was seen. Mice fed with HFCD when compared to CD had much less NK cells both in WT and KC mice in pancreas, adipose and gingiva.ConclusionMice fed with HFCD exhibited higher inflammatory index when compared to those fed with CD both in WT and KC mice. In addition, numbers and the cytotoxicity of NK cells were severely decreased in pancreas and gingiva of WT and KC mice fed with HFCD. High fat diet exacerbates the progression of neoplastic lesions in KC mice and could be responsible for the oral mucosa pathologies due to decrease function and numbers of key immune effectors.Support or Funding InformationP01 CA163200; PAPD and XO clubThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice.

Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.

Lipid droplet dynamics and insulin sensitivity upon a 5-day high-fat diet in Caucasians and South Asians

A 5-day High-Fat High-Calorie diet (HFHC-diet) reduces insulin-stimulated glucose disposal (Rd) in South Asian, but not Caucasian healthy lean males. We aimed to investigate if differences in myocellular lipid handling are underlying this differential response. A two-step hyperinsulinemic-euglycemic clamp and muscle biopsies were performed in 12 healthy lean Caucasian and South Asian males (BMI < 25 kg/m2, 19–25 years) before and after a 5-day HFHC-diet (regular diet + 375 mL cream/day; 1275 kcal/day; 94% fat). Triglyceride extractions and Western Blots for lipid droplet and mitochondrial proteins were performed. Intramyocellular lipid content and HFHC-diet response were similar between ethnicities (group effect: P = 0.094; diet effect: +~30%, P = 0.044). PLIN5 protein content increased upon the HFHC-diet (P = 0.031) and tended to be higher in South Asians (0.87 ± 0.42 AU vs. 1.35 ± 0.58 AU, P = 0.07). 4-HNE tended to increase in South Asians upon the HFHC-diet (interaction effect: P = 0.057). In Caucasians ΔPLIN5 content correlated with ΔRd (Caucasians: r = 0.756, P = 0.011; South Asians: r = −0.085, P = 0.816), while in South Asians Δ4-HNE associated with ΔPLIN5 content (Caucasians: r = 0.312, P = 0.380; South Asians: r = 0.771, P = 0.003). These data indicate that in Caucasians, PLIN5 may be protective against HFHC-diet induced insulin resistance, which for reasons not yet understood is not observed in South Asians, who possess increased lipid peroxidation levels.

Robust Early Inflammation of the Peripancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer.

Obesity increases the incidence of multiple types of cancer. Our previous work has shown that a high-fat, high-calorie diet (HFCD) leads to visceral obesity, pancreatic inflammation, and accelerated pancreatic neoplasia in KrasG12D (KC) mice. In this study, we aimed to investigate the effects of an HFCD on visceral adipose inflammation with emphasis on potential differences between distinct visceral adipose depots. We examined the weight and visceral obesity in both wild-type and KC mice on either control diet (CD) or HFCD. After 3 months, mice were killed for histological examination. Multiplex assays were also performed to obtain cytokine profiles between different adipose depots. Both wild-type and KC mice on an HFCD exhibited significantly increased inflammation in the visceral adipose tissue, particularly in the peripancreatic fat (PPF), compared with animals on a CD. This was associated with significantly increased inflammation in the pancreas. Cytokine profiles were different between visceral adipose depots and between mice on the HFCD and CD. Our results clearly demonstrate that an HFCD leads to obesity and inflammation in the visceral adipose tissue, particularly the PPF. These data suggest that obesity-associated inflammation in PPF may accelerate pancreatic neoplasia in KC mice.

Abstract 3163: Diet-induced obesity is associated with increased levels of IL-4 and IL-13, macrophage infiltration, fibrosis, and pancreatic neoplasia in the conditional KrasG12D mouse model

Abstract Background: Obesity is a well known risk factor for the development of several cancers including pancreatic cancer (PaCa). The formation of an inflammatory microenvironment with a complex communication between (pre)-neoplastic cells and stromal cells, including fibroblasts and inflammatory cells, is thought to promote tumor development during obesity. However, the exact molecular signals that are critical in this process are unknown. Recently, there has been interest in understanding the role of interleukins (IL)-4 and -13 in mediating the crosstalk between several cell types in cancer. E.g. they have been shown to promote the conversion of anti-tumorigenic M1 macrophages to pro-tumorigenic M2 macrophages. Aim: In this study we sought to investigate whether diet-induced obesity in the conditional KrasG12D mouse model of PaCa is associated with enhanced fibrosis and inflammation in the pancreas and to determine a possible role of IL-4 and -13. Methods and Results: Conditional KrasG12D mice and wildtype controls were fed a high fat, high calorie diet (HFCD) or control diet (CD) for 3 months. Mice fed the HFCD gained significantly more weight with a substantial enlargement of the visceral adipose tissue. Mutant mice fed the HFCD had more advanced pancreatic intraepithelial neoplasia lesions (PanINs). Compared to CD, mice fed the HFCD had a significant increase in pancreatic fibrosis (3.0±0.7 fold) and enhanced activation of pancreatic stellate cells (1.9±0.2) as assessed by immunohistochemical staining for fibronectin and α-smooth muscle actin, respectively. Flow cytometry demonstrated increased infiltration of Gr-CD11b+ macrophages (2.0±0.4 fold) into the pancreas in mice fed the HFCD. In addition, compared to the CD the HFCD was associated with increased tissue levels of IL-4 (43±5%) and IL-13 (65±20%) in the pancreas. Conclusion: Our results demonstrate that diet-induced obesity was associated with enhanced pancreatic neoplasia, inflammation, and fibrosis in the conditional KrasG12D mouse model. Our data further show that IL-4 and IL-13 are elevated in the pancreas of obese mice suggesting that these cytokines play a role, possibly in conversion of macrophages to the pro-tumorigenic M2 phenotype thereby promoting inflammation and tumor development. Citation Format: Chiara Birtolo, Guido Eibl, Aune Moro, Xiaoman Jung, Susan Morvaridi, Richard Waldron, Aurelia Lugea, Vay LW Go, Stephen J. Pandol. Diet-induced obesity is associated with increased levels of IL-4 and IL-13, macrophage infiltration, fibrosis, and pancreatic neoplasia in the conditional KrasG12D mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3163. doi:10.1158/1538-7445.AM2015-3163

A 5-Day High-Fat, High-Calorie Diet Impairs Insulin Sensitivity in Healthy, Young South Asian Men but Not in Caucasian Men

South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

HIGHLIGHTS FROM THE LITERATURE

HIGHLIGHTS FROM THE LITERATURE

Angptl3-null Mice Show Low Plasma Lipid Concentrations by Enhanced Lipoprotein Lipase Activity

Angiopoietin-like 3 (ANGPTL3) is a secreted protein with both angiogenesis and lipid metabolism functions. We generated knockout mice that failed to express the Angptl3 gene, and analyzed the lipid metabolism. Angptl3-null mice, fed a normal diet or a high-fat, high-calorie (HFC) diet, revealed markedly low plasma lipid concentrations, especially plasma triglyceride concentration, although the body weight and liver weight were not different between Angptl3-null mice and wild-type mice. Angptl3-null mice fed an HFC diet also revealed a significantly reduced epididymal adipose tissue weight despite there being no difference in adipocyte size between them and wild-type mice. A triglyceride clearance study indicated that the lower plasma triglyceride concentration in Angptl3-null mice was caused by an accelerated clearance of triglyceride. In fact, lipoprotein lipase and hepatic lipase activities in the post-heparin plasma of Angptl3-null mice were 1.57 times and 1.42 times higher than those of wild-type mice, respectively. These results suggest that ANGPTL3 may have an effect not only on lipid metabolism but also on adipose formation.