Short-term High-fat Diet Feeding Research Articles

Interindividual differences of dietary fat-inducible Mest in white adipose tissue of C57BL/6J mice are not heritable.

Differences in white adipose tissue (WAT) expression of mesoderm-specific transcript (Mest) in C57BL6/J mice fed a high-fat diet (HFD) are concomitant with and predictive for the development of obesity. However, the basis for differences in WAT Mest among mice is unknown. This study investigated whether HFD-inducible WAT Mest, as well as susceptibility to obesity, is transmissible from parents to offspring. WAT biopsies of mice fed an HFD for 2 weeks identified parents with low and high WAT Mest for breeding. Obesity phenotypes, WAT Mest, hepatic gene expression, and serum metabolites were determined in offspring fed an HFD for 2 weeks. Offspring showed no heritability of obesity or WAT Mest phenotypes from parents but did show hepatic and serum metabolite changes consistent with their WAT Mest. Importantly, retired male breeders showed WAT Mest expression congruent with initial WAT biopsies even though HFD exposure occurred early in life. Disparity of HFD-induced Mest in mice is not heritable but, rather, is reestablished during each generation and remains fixed from an early age to adulthood. Short-term HFD feeding reveals variation of WAT Mest expression within isogenic mice that is positively associated with the development of obesity.

Aldose Reductase (AR) Mediates and Perivascular Adipose Tissue (PVAT) Modulates Endothelial Dysfunction of Short-Term High-Fat Diet Feeding in Mice.

Increased adiposity of both visceral and perivascular adipose tissue (PVAT) depots is associated with an increased risk of diabetes and cardiovascular disease (CVD). Under healthy conditions, PVAT modulates vascular tone via the release of PVAT-derived relaxing factors, including adiponectin and leptin. However, when PVAT expands with high-fat diet (HFD) feeding, it appears to contribute to the development of endothelial dysfunction (ED). Yet, the mechanisms by which PVAT alters vascular health are unclear. Aldose reductase (AR) catalyzes glucose reduction in the first step of the polyol pathway and has been long implicated in diabetic complications including neuropathy, retinopathy, nephropathy, and vascular diseases. To better understand the roles of both PVAT and AR in HFD-induced ED, we studied structural and functional changes in aortic PVAT induced by short-term HFD (60% kcal fat) feeding in wild type (WT) and aldose reductase-null (AR-null) mice. Although 4 weeks of HFD feeding significantly increased body fat and PVAT mass in both WT and AR-null mice, HFD feeding induced ED in the aortas of WT mice but not of AR-null mice. Moreover, HFD feeding augmented endothelial-dependent relaxation in aortas with intact PVAT only in WT and not in AR-null mice. These data indicate that AR mediates ED associated with short-term HFD feeding and that ED appears to provoke 'compensatory changes' in PVAT induced by HFD. As these data support that the ED of HFD feeding is AR-dependent, vascular-localized AR remains a potential target of temporally selective intervention.

Short-term high-fat diet feeding induces cognitive decline, aggressiveness and anxiety-like behavior in adult zebrafish (Danio rerio)

Short-term high-fat diet feeding induces cognitive decline, aggressiveness and anxiety-like behavior in adult zebrafish (Danio rerio)

Cellular cholesterol homeostasis supports visceral adipose tissue (VAT) regulatory T cell (Treg) accumulation and promotes metabolic health

Abstract A unique population of regulatory T cells (Tregs), characterized by a clonally expanded TCR repertoire and distinct transcriptional profile, is highly enriched in the visceral adipose tissue (VAT) at steady state but is lost during obesity, which exacerbates VAT inflammation and promotes metabolic disease. Therefore, understanding the factors that control the accumulation of VAT Tregs, which might be dysregulated during obesity, is important for developing novel therapies for obesity-associated metabolic diseases. Here we show that cellular cholesterol homeostasis is particularly important for VAT Treg accumulation and function. First, bulk RNA sequencing analysis of VAT Tregs from mice fed long-term high fat diet (HFD) showed a reduction in gene expression involved in cholesterol homeostasis (CH), corresponding to loss of VAT Tregs in vivo. Second, we found that VAT Tregs showed increased cholesterol-associated gene expression, cholesterol levels, and cholesterol uptake compared to lymphoid Tregs at steady state, suggesting this pathway is particularly important for VAT Tregs. Third, CRISPR-Cas9-mediated ablation of Srebf2, the master regulator of cholesterol homeostasis, followed by adoptive Treg transfer or Treg-specific germline deletion of Srebf2(Foxp3cre Srebf2-flox) reduced Tregs in the VAT, but not those in other tissues. Deletion of Srebf2in Tregs also increased VAT inflammatory cytokine expression, inflammatory cell infiltration, and insulin resistance in mice following short-term HFD feeding. These data highlight an importance of cellular CH for VAT Treg accumulation and function and implicate this pathway as a potential therapeutic target for treatment of obesity-associated metabolic diseases. NIH R01 (5R01DK128061-02)

Short-term high-fat diet feeding of mice suppresses catecholamine-stimulated Ca2+ signalling in hepatocytes and intact liver.

Excess consumption of carbohydrates, fat and calories leads to non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; these are major factors in the pathogenesis of type II diabetes. Hormones and catecholamines acting through G-protein coupled receptors (GPCRs) linked to phospholipase C (PLC) and increases in cytosolic Ca2+ ([Ca2+ ]c ) regulate many metabolic functions of the liver. In the intact liver, catabolic hormones such as glucagon, catecholamines and vasopressin integrate and synergize to regulate the frequency and extent to which [Ca2+ ]c waves propagate across hepatic lobules to control metabolism. Dysregulation of hepatic Ca2+ homeostasis has been implicated in the development of metabolic disease, but changes in hepatic GPCR-dependent Ca2+ signalling have been largely unexplored in this context. We show that short-term, 1-week, high-fat diet (HFD) feeding of mice attenuates noradrenaline-stimulated Ca2+ signalling, reducing the number of cells responding and suppressing the frequency of [Ca2+ ]c oscillations in both isolated hepatocytes and intact liver. The 1-week HFD feeding paradigm did not change basal Ca2+ homeostasis; endoplasmic reticulum Ca2+ load, store-operated Ca2+ entry and plasma membrane Ca2+ pump activity were unchanged compared to low-fat diet (LFD)-fed controls. However, noradrenaline-induced inositol 1,4,5-trisphosphate production was significantly reduced after HFD feeding, demonstrating an effect of HFD on receptor-stimulated PLC activity. Thus, we have identified a lesion in the PLC signalling pathway induced by short-term HFD feeding, which interferes with hormonal Ca2+ signalling in isolated hepatocytes and the intact liver. These early events may drive adaptive changes in signalling, which lead to pathological consequences in fatty liver disease. KEY POINTS: Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic. In healthy liver, the counteracting effects of catabolic and anabolic hormones regulate metabolism and energy storage as fat. Hormones and catecholamines promote catabolic metabolism via increases in cytosolic Ca2+ ([Ca2+ ]c ). We show that 1week high-fat diet (HFD) feeding of mice attenuated the Ca2+ signals induced by physiological concentrations of noradrenaline. Specifically, HFD suppressed the normal pattern of periodic [Ca2+ ]c oscillations in isolated hepatocytes and disrupted the propagation of intralobular [Ca2+ ]c waves in the intact perfused liver. Short-term HFD inhibited noradrenaline-induced inositol 1,4,5-trisphosphate generation, but did not change basal endoplasmic reticulum Ca2+ load or plasma membrane Ca2+ fluxes. We propose that impaired Ca2+ signalling plays a key role in the earliest phases of the etiology of NAFLD, and is responsible for many of the ensuing metabolic and related dysfunctional outcomes at the cellular and whole tissue level.

Diet-induced obesity worsens allergen-induced type 2/type 17 inflammation in airways by enhancing DUOX1 activation.

More than 50% of people with asthma in the United States are obese, and obesity often worsens symptoms of allergic asthma and impairs response to treatment. Based on previously established roles of the epithelial NADPH oxidase DUOX1 in allergic airway inflammation, we addressed the potential involvement of DUOX1 in altered allergic inflammation in the context of obesity. Intranasal house dust mite (HDM) allergen challenge of subjects with allergic asthma induced rapid secretion of IL-33, then IL-13, into the nasal lumen, responses that were significantly enhanced in obese asthmatic subjects (BMI >30). Induction of diet-induced obesity (DIO) in mice by high-fat diet (HFD) feeding similarly enhanced acute airway responses to intranasal HDM challenge, particularly with respect to secretion of IL-33 and type 2/type 3 cytokines, and this was associated with enhanced epithelial DUOX1 expression and was avoided in DUOX1-deficient mice. DIO also enhanced DUOX1-dependent features of chronic HDM-induced allergic inflammation. Although DUOX1 did not affect overall weight gain by HFD feeding, it contributed to glucose intolerance, suggesting a role in glucose metabolism. However, glucose intolerance induced by short-term HFD feeding, in the absence of adiposity, was not sufficient to alter HDM-induced acute airway responses. DIO was associated with enhanced presence of the adipokine leptin in the airways, and leptin enhanced DUOX1-dependent IL-13 and mucin production in airway epithelial cells. In conclusion, augmented inflammatory airway responses to HDM in obesity are associated with increases in airway epithelial DUOX1, and by increased airway epithelial leptin signaling.

SMP30-mediated synthesis of vitamin C activates the liver PPARα/FGF21 axis to regulate thermogenesis in mice

The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.

Methionine Restriction Affects Metabolic Parameters in a Fibroblast Growth Factor 21- and Sex-Dependent Manner

ObjectivesIn rodents, dietary restriction of the amino acid methionine produces profound protection against obesity and obesity-related comorbidities. Fibroblast growth factor 21 (FGF21) is now recognized as an important mediator of methionine restriction's (MR) metabolic benefits. Most preclinical work investigating the impact of diet on weight gain and metabolism has been conducted in males, leaving a gap in our understanding of female responses to dietary changes. This study aimed to examine the impact of high-fat diet (HFD) feeding and MR on body weight and adiposity in male and female mice. Furthermore, we sought to determine the sex-dependent role of endogenous FGF21 in mediating metabolic responses to HFD and MR.MethodsMale and female wild-type (WT) and Fgf21 knockout (Fgf21−/−) mice were fed low-fat diet (LFD) or HFD versions of control (0.86% methionine) or MR (0.17% methionine) diets for 5 weeks. Average body weight (BW) and food intake were recorded weekly. Insulin tolerance tests were performed at week 4. After 5 weeks, mice were euthanized, and adipose depots were collected.ResultsNeither HFD nor MR significantly altered BW of female mice regardless of genotype. However, while HFD did not significantly affect BW, MR significantly reduced BW of both WT and Fgf21−/− males (p < 0.0001). Neither HFD nor MR significantly altered adiposity (gonadal adipose tissue weight/body weight) in female mice regardless of genotype. However, HFD significantly increased adiposity in male WT and Fgf21−/− mice, and MR prevented this increase in both genotypes. MR increased energy intake in LFD- and HFD-fed WT mice. The ability of MR to increase energy intake was abolished in LFD- and HFD-fed Fgf21−/− mice.ConclusionsThe effects of MR on BW and adiposity are sex-dependent, but FGF21-independent. Short-term HFD feeding affects adiposity differently in males and females. The effects of MR on energy intake are dependent upon FGF21. As the field progresses towards developing FGF21 as a therapeutic agent, it will be essential to understand its impact on both sexes.Funding SourcesSources Center for Neuroinflammation and Cardiometabolic Diseases Seed Grant.

Early decrease in Cx36 is associated with increased cell adhesion molecules (CAMs) junctional content in mouse pancreatic islets after short-term high-fat diet feeding

Cell-to-cell interactions mediated by intercellular junctions (IJs) are crucial for beta-cell functioning and proper insulin secretion, however, their role in type-2 diabetes is still unclear. This work aimed to evaluate the cellular distribution and expression of proteins associated with adherens (AJs) and gap junctions (GJs) in pancreatic islets of C57BL6 mice fed a high-fat (HF) diet. The administration of HF diet for 30 days induced an increase in body weight, post-prandial glycemia, insulinemia, glucose intolerance, and moderate insulin resistance associated with mild perturbations in insulin secretion. The intercellular content of the AJ-associated proteins (namely, E-, N-cadherins, and α-, β-catenins) was significantly higher in islet cells of HF-fed mice. Inversely, the gap junctional content of Cx36 was significantly decreased, as revealed by immunofluorescence, which was paralleled by a reduction in the frequency of calcium oscillations in islets of prediabetic mice. In conclusion, the endocrine pancreas displays significant changes in the content of several junctional proteins at the cell-cell contact region following short-term HF diet administration, indicating that IJs may be involved in the adaptive response of beta cells seen during this state.

Prominent hypertrophy of perivascular adipocytes due to short-term high fat diet

Excessive lipid accumulation is a serious problem in obesity leading to adipose tissue (AT) overgrowth, chronic inflammation, endothelial dysfunction, and elevated risk of cardiovascular complications. In this work, Raman techniques coupled with fluorescence imaging were applied to characterize the effects of short-term (2 weeks) and extended (up to 8 weeks) high-fat diet (HFD) feeding on various depots of the adipose tissue of young and mature mice. Our results proved the synergistic effect of age and HFD-induced obesity manifested by changes in the morphology of adipocytes and the chemical composition of lipids. After 2 weeks of HFD feeding of young animals, substantial hypertrophy of adipocytes but only for the periaortic adipose tissue was detected with a significant decrease in lipid unsaturation degree solely in the epididymal white adipose tissue. The periaortic AT did not altered chemically due to short-term HFD feeding, however, it changed with age and with prolonged exposure to harmful factors. For older animals only brown AT remains resistant on HFD underlying its protective role and highlighting its potential as a target in obesity therapies.

Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation

A high-fat diet (HFD) can induce hyperglycemia and metabolic syndromes that, in turn, can trigger visual impairment. To evaluate the acute effects of HFD feeding on retinal degeneration, we assessed retinal function and morphology, inflammatory state, oxidative stress, and gut microbiome in dystrophic retinal degeneration 10 (rd10) mice, a model of retinitis pigmentosa, fed an HFD for 2 to 3 wk. Short-term HFD feeding impaired retinal responsiveness and visual acuity and enhanced photoreceptor degeneration, microglial cell activation, and Müller cell gliosis. HFD consumption also triggered the expression of inflammatory and oxidative markers in rd10 retinas. Finally, an HFD caused gut microbiome dysbiosis, increasing the abundance of potentially proinflammatory bacteria. Thus, HFD feeding drives the pathological processes of retinal degeneration by promoting oxidative stress and activating inflammatory-related pathways. Our findings suggest that consumption of an HFD could accelerate the progression of the disease in patients with retinal degenerative disorders.

Short-term but not long-term high fat diet feeding protects against pressure overload-induced heart failure through activation of mitophagy

AimsRecent studies have shown that enhancement of fatty acid utilization through feeding animals a high fat diet (HFD) attenuated cardiac dysfunction in heart failure (HF). Here, we aimed to examine the temporal effects of HFD feeding on cardiac function in mice with heart failure and its underlying mechanism. Main methodsPressure overload-induced HF was established via transverse aortic constriction (TAC) surgery. After surgery, the mice were fed on either normal diet or HFD for 8 or 16 weeks. Key findingsHFD feeding exerted opposite effects on cardiac function at different time points post-surgery. Short-term HFD feeding (8 wk) protected the heart against pressure overload, inhibiting cardiac hypertrophy and improving cardiac function, while long-term HFD feeding (16 wk) aggravated cardiac dysfunction in TAC mice. Short-term HFD feeding elevated cardiac fatty acid utilization, while long-term HFD feeding showed no significant effects on cardiac fatty acid utilization in TAC mice. Specifically, an increase in cardiac fatty acid utilization was accompanied with activated mitophagy and improved mitochondrial function. Palmitic acid treatment (400 μM, 2 h) stimulated fatty acid oxidation and mitophagy in neonatal myocytes. Mechanistically, fatty acid utilization stimulated mitophagy through upregulation of Parkin. Cardiac-specific knockdown of Parkin abolished the protective effects of short-term HFD feeding on cardiac function in TAC mice. SignificancesThese results suggested that short-term but not long-term HFD feeding protects against pressure overload-induced heart failure through activation of mitophagy, and dietary fat intake should be used with caution in treatment of heart failure.

Impaired Glucose Tolerance is Associated with Enhanced Platelet-Monocyte Aggregation in Short-Term High-Fat Diet-Fed Mice.

High-fat diet (HFD) feeding is known to induce metabolic dysregulation, however, less is known on its impact in promoting the hypercoagulable state. This current study aimed to evaluate platelet-monocyte aggregate (PMA) formation following short-term HFD feeding. This is particularly important for understanding the link between inflammation and the hypercoagulable state during the early onset of metabolic dysregulation. To explore such a hypothesis, mice were fed a HFD for 8 weeks, with body weights as well as insulin and blood glucose levels monitored on a weekly basis during this period. Basal hematological measurements were determined and the levels of spontaneous peripheral blood PMAs were assessed using whole blood flow cytometry. The results showed that although there were no significant differences in body weights, mice on HFD displayed impaired glucose tolerance and markedly raised insulin levels. These metabolic abnormalities were accompanied by elevated baseline PMA levels as an indication of hypercoagulation. Importantly, it was evident that baseline levels of monocytes, measured using the CD14 monocyte marker, were significantly decreased in HFD-fed mice when compared to controls. In summary, the current evidence shows that in addition to causing glucose intolerance, such as that identified in a prediabetic state, HFD-feeding can promote undesirable hypercoagulation, the major consequence implicated in the development of cardiovascular complications.

Hepatic insulin sensitivity is improved in high-fat diet-fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis.

Park2 is an E3 ubiquitin ligase known for its role in mitochondrial quality control via the mitophagy pathway. Park2 KO mice are protected from diet‐induced obesity and hepatic insulin sensitivity is improved in high‐fat diet (HFD)‐fed Park2 KO mice even under body weight‐matched conditions. In order to better understand the cellular mechanism by which Park2 KO mice are protected from diet‐induced hepatic insulin resistance, we determined changes in multiple pathways commonly associated with the pathogenesis of insulin resistance, namely levels of bioactive lipid species, activation of the endoplasmic reticulum (ER) stress response and changes in cytokine levels and signaling. We report for the first time that whole‐body insulin sensitivity is unchanged in regular chow (RC)‐fed Park2 KO mice, and that liver diacylglycerol levels are reduced and very‐long‐chain ceramides are increased in Park2 KO mice fed HFD for 1 week. Hepatic transcriptional markers of the ER stress response were reduced and plasma tumor necrosis factor‐α (TNFα), interleukin‐6 and −10 (IL6, IL10) were significantly increased in HFD‐fed Park2 KO mice; however, there were no detectable differences in hepatic inflammatory signaling pathways between groups. Interestingly, hepatic adenylate charge was reduced in HFD‐fed Park2 KO liver and was associated increased activation of AMPK. These data suggest that negative energy balance that contributed to protection from obesity during chronic HFD manifested at the level of the hepatocyte during short‐term HFD feeding and contributed to the improved hepatic insulin sensitivity.

Mice lacking DGKε show increased beige adipogenesis in visceral white adipose tissue after long-term high fat diet in a COX-2- dependent manner.

Adipose tissue is a central site for energy storage in the form of triglyceride (TG). Under excess energy conditions, TG is synthesized by acylation of diacylglycerol (DG), whereas TG is broken down into DG and free fatty acid, which provide energy for mitochondrial lipid oxidation when needed. In this regard, DG is not merely an intermediate metabolite for TG metabolism; it also serves as a signaling molecule. DG kinase (DGK) phosphorylates DG to produce phosphatidic acid (PA). Consequently, DGK plays a pivotal role in the control of lipid metabolism and signal transduction pathway. Recently, a report has described that DGKε-knockout (KO) mice show expansion of epididymal white adipose tissue (WAT) together with the impairment of glucose clearance after short-term (40 days) high fat diet (HFD) feeding, an early presymptomatic phase of obesity in wild-type animals. Nevertheless, no report describes an investigation of their phenotype under long-term HFD feeding conditions. Remarkably, results obtained during long-term HFD feeding show that WAT mass is decreased significantly and that the blood glucose profile in response to glucose challenge is improved in DGKε-KO mice compared with wild-type, which contrast sharply against the phenotype shown for short-term HFD feeding. Morphological examination reveals that cyclooxygenase-2 (COX-2) expression and clusters of uncoupling protein 1 (UCP1)-positive multilocular brown-like ("beige") adipocyte are induced in DGKε-deficient WAT after long-term HFD feeding, suggesting that beige adipocytes facilitate energy expenditure during prolonged HFD feeding. Administration of celecoxib, a selective inhibitor of COX-2, abolishes the appearance of UCP1-positive beige adipocytes in DGKε-KO mice. These findings suggest that DGKε deficiency promotes visceral WAT remodeling in a COX-2-dependent manner under long-term HFD feeding conditions.

Short-term high-fat diet feeding protects from the development of experimental allergic asthma in mice.

A close association between obesity and asthma has been described. The nature of this association remains elusive, especially with respect to allergic asthma. Controversial findings exist regarding the impact of short-term high-fat diet (HFD) feeding on the development of allergic asthma. To delineate the impact of short-term HFD feeding on the development of experimental allergic asthma. Female C57BL/6JRJ mice were fed with a short-term HFD or chow diet (CD) for 12weeks. Allergic asthma was induced by intraperitoneal OVA/alum sensitization followed by repeated OVA airway challenges. We determined airway hyperresponsiveness (AHR) and pulmonary inflammation by histologic and flow cytometric analysis of immune cells. Furthermore, we assessed the impact of HFD on dendritic cell (DC)-mediated activation of T cells. Female mice showed a mild increase in body weight accompanied by mild metabolic alterations. Upon OVA challenge, CD-fed mice developed strong AHR and airway inflammation, which were markedly reduced in HFD-fed mice. Mucus production was similar in both treatment groups. OVA-induced increases in DC and CD4+ T-cell recruitment to the lungs were significantly attenuated in HFD-fed mice. MHC-II expression and CD40 expression in pulmonary CD11b+ DCs were markedly lower in HFD-fed compared to CD-fed mice, which was associated in vivo with a decreased T helper (Th) 1/17 differentiation and Treg formation without impacting Th2 differentiation. These findings suggest that short-term HFD feeding attenuates the development of AHR, airway inflammation, pulmonary DC recruitment and MHC-II/CD40 expression leading to diminished Th1/17 but unchanged Th2 differentiation. Thus, short-term HFD feeding and associated metabolic alterations may have protective effects in allergic asthma development.

Short-term high-fat diet modulates several inflammatory, ER stress, and apoptosis markers in the hippocampus of young mice

The consumption of saturated fatty acids is one of the leading risk factors for Alzheimer’s Disease (AD) development. Indeed, the short-term consumption of a high-fat diet (HFD) is related to increased inflammatory signals in the hippocampus; however, the potential molecular mechanisms linking it to AD pathogenesis are not fully elucidated. In our study, we investigated the effects of short-term HFD feeding (within 3, 7 and 10 days) in AD markers and neuroinflammation in the hippocampus of mice. The short period of HFD increased fasting glucose and HOMA-IR. Also, mice fed HFD increased the protein content of β-Amyloid, pTau, TNFα, IL1β, pJNK, PTP1B, peIF2α, CHOP, Caspase3, Cleaved-Caspase3 and Alzheimer-related genes (Bax, PS1, PEN2, Aph1b). At 10 days, both neuronal (N2a) and microglial (BV2) cells presented higher expression of inflammatory and apoptotic genes when stimulated with palmitate. These findings suggest that a short period of consumption of a diet rich in saturated fat is associated with activation of inflammatory, ER stress and apoptotic signals in the hippocampus of young mice.

Group VIA phospholipase A2 deficiency in mice chronically fed with high-fat-diet attenuates hepatic steatosis by correcting a defect of phospholipid remodeling

A defect of hepatic remodeling of phospholipids (PL) is seen in non-alcoholic fatty liver disease and steatohepatitis (NASH) indicating pivotal role of PL metabolism in this disease. The deletion of group VIA calcium-independent phospholipase A2 (iPla2β) protects ob/ob mice from hepatic steatosis (BBAlip 1861, 2016, 440–461), however its role in high-fat diet (HFD)-induced NASH is still elusive. Here, wild-type and iPla2β-null mice were subjected to chronic feeding with HFD for 6 months. We showed that protection was observed in iPla2β-null mice with an attenuation of diet-induced body and liver-weight gains, liver enzymes, serum free fatty acids as well as hepatic TG and steatosis scores. iPla2β deficiency under HFD attenuated the levels of 1-stearoyl lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and lysophosphatidylinositol (LPI) as well as elevation of hepatic arachidonate, arachidonate-containing cholesterol esters and prostaglandin E2. More importantly, this deficiency rescued a defect in PL remodeling and attenuated the ratio of saturated and unsaturated PL. The protection by iPla2β deficiency was not observed during short-term HFD feeding of 3 or 5 weeks which showed no PL remodeling defect. In addition to PC/PE, this deficiency reversed the suppression of PC/PI and PE/PI among monounsaturated PL. However, this deficiency did not modulate hepatic PL contents and PL ratios in ER fractions, ER stress, fibrosis, and inflammation markers. Hence, iPla2β inactivation protected mice against hepatic steatosis and obesity during chronic dietary NASH by correcting PL remodeling defect and PI composition relative to PC and PE.

Impaired adaptation of energy intake induces severe obesity in aged mice on a high-fat diet.

High‐fat diet (HFD) feeding induces inflammation in various tissues, including the nodose ganglion and hypothalamus, resulting in obesity and metabolic disorders. In this study, we investigated the effect of short‐term HFD on aged and young mice. Aged mice easily gained weight during short‐term HFD feeding, and required many days to adapt their energy intake. One‐day HFD in aged mice induced inflammation in the distal colon, but not in the nodose ganglion or hypothalamus. The anorexic effect of glucagon‐like peptide‐1 (GLP‐1) was attenuated in aged mice. Intraperitoneal administration of GLP‐1 did not induce expression of genes that regulate feeding in the hypothalamus of aged mice. mRNA expression of the gene encoding the GLP‐1 receptor (Glp1r) in the nodose ganglion was significantly lower in aged mice than in young mice. Our findings suggest that adaptation of energy intake regulation was attenuated in aged mice, causing them to become obese in response to short‐term HFD feeding.

Er-Miao-Fang Extracts Inhibits Adipose Lipolysis and Reduces Hepatic Gluconeogenesis via Suppression of Inflammation.

High-fat-diet (HFD) feeding induces adipose dysfunction. This study aims to explore whether the Traditional Chinese Medical prescription Er-Miao-Fang could ameliorate adipose dysfunction and prevent hepatic glucose output. Short-term HFD feeding induced adipose lipolysis accompanied with enhanced hepatic glucose output in mice. Adipose lipolysis is initiated by cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling. Oral administration Er-Miao-Fang inhibited inflammation in adipose tissue by dephosphorylation of JNK and reducing TNF-α and IL-1β production, and thus preserved phosphodiesterase 3B (PDE3B) induction, contributing to preventing cAMP accumulation. As a result, from suppression of PKA activation, Er-Miao-Fang reduced fatty acids and glycerol release from adipose tissue due to the inhibition hormone-sensitive lipase (HSL). By blocking the traffic of fatty acids and inflammatory mediators from adipose tissue to the liver, Er-Miao-Fang attenuated hepatic cAMP/PKA signaling by protecting phosphodiesterase 4B (PDE4B) induction from inflammatory insult, and thereby reduced hepatic glucose production by suppression of hepatic glucagon response in HFD-fed mice. In conclusion, Er-Miao-Fang prevented adipose lipolysis by suppression of inflammation, contributing to reducing excessive hepatic glucose output. These findings present a new view of regulating gluconeogenesis and provide the guiding significance for the regulation of multi-link targets with Traditional Chinese Medicine.