High fat diet alters lactation outcomes: possible involvement of inflammatory and serotonergic pathways

Delay in the onset of lactogenesis has been shown to occur in women who are obese, however the mechanism altered within the mammary gland causing the delay remains unknown. Consumption of high fat diets (HFD) has been previously determined to result decreased litters and litter numbers in rodent models due to a decrease in fertility. We examined the effects of feeding a HFD (60% kcal from fat) diet versus a low-fat diet (LFD; 10% kcal from fat) to female Wistar rats on lactation outcomes. Feeding of HFD diet resulted in increased pup weights compared to pups from LFD fed animals for 4 d post-partum. Lactation was delayed in mothers on HFD but they began to produce copious milk volumes beginning 2 d post-partum, and milk yield was similar to LFD by day 3. Mammary glands collected from lactating animals on HFD diet, displayed a disrupted morphologies, with very few and small alveoli. Consistently, there was a significant decrease in the mRNA expression of milk protein genes, glucose transporter 1 (GLUT1) and keratin 5 (K5), a luminobasal cell marker in the mammary glands of HFD lactating animals. Expression of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in serotonin (5-HT) biosynthesis, and the 5-HT(7) receptor (HTR7), which regulates mammary gland involution, were significantly increased in mammary glands of HFD animals. Additionally, we saw elevation of the inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These results indicate that consumption of HFD impairs mammary parenchymal tissue and impedes its ability to synthesize and secrete milk, possibly through an increase in 5-HT production within the mammary gland leading to an inflammatory process.     

Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow

Rats offered chow, lard, and 30% sucrose solution (choice) rapidly become obese. We tested metabolic disturbances in rats offered choice, chow+lard, or chow+30% sucrose solution [chow+liquid sucrose (LS)] and compared them with rats fed a composite 60% kcal fat, 7% sucrose diet [high-fat diet (HFD)], or a 10% kcal fat, 35% sucrose diet [low-fat diet (LFD)]. Choice rats had the highest energy intake, but HFD rats gained the most weight. After 23 days carcass fat was the same for choice, HFD, chow+lard, and chow+LS groups. Glucose clearance was the same for all groups during an intraperitoneal glucose tolerance test (GTT) on day 12, but fasting insulin was increased in choice, LFD fed, and chow+LS rats. By contrast, only choice and chow+LS rats were resistant to an intraperitoneal injection of 2 mg leptin/kg on day 17. In experiment 2 choice rats were insulin insensitive during an intraperitoneal GTT, but this was corrected in an oral GTT due to GLP-1 release. UCP-1 protein was increased in brown fat and inguinal white fat in choice rats, and this was associated with a significant increase in energy expenditure of choice rats during the dark period whether expenditure was expressed on a per animal or a metabolic body size basis. The increase in expenditure obviously was not great enough to prevent development of obesity. Further studies are required to determine the mechanistic basis of the rapid onset of leptin resistance in choice rats and how consumption of sucrose solution drives this process.     

Effect of Diet‐induced Obesity on Acute Pancreatitis Induced by Administration of Interleukin‐12 Plus Interleukin‐18 in Mice

Obesity is associated with increased severity of acute pancreatitis (AP). We recently developed a model of AP induced by administration of interleukin (IL)‐12+IL‐18, two cytokines that are elevated in patients with AP. In this model, severe AP develops in obese leptin‐deficient ob/ob mice compared to lean littermates. In the present report, we evaluated the pancreatic response of diet‐induced obesity (DIO) mice to IL‐12+IL‐18. Body weight loss and adipose tissue necrosis were more severe and prolonged in cytokine‐injected DIO compared to lean mice. Edematous AP developed in lean mice, whereas DIO mice developed necrotizing AP. Obese DIO mice developed more severe hypocalcemia, increased liver damage and a heightened acute‐phase response compared to lean mice, although leukopenia and thrombocytopenia were of comparable severity in lean and DIO mice. Serum levels of IL‐6, IL‐10, and IL‐22 were significantly higher in DIO compared to lean mice, whereas interferon‐γ and tumor necrosis factor‐α did not differ between the two groups. In conclusion, obesity induced by high‐fat diet is associated with increased disease severity and duration in the model of AP induced by administration of IL‐12+IL‐18.     

Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet

To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH(2)-terminal POMC transgene that includes alpha- and gamma(3)-MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.     

Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice

Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.     

Trichinella spiralis infection ameliorated diet-induced obesity model in mice

Obesity is an increasingly prevalent disease worldwide, and genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases. Emerging studies indicate that innate and adaptive immune cell responses in adipose tissue play critical roles in the regulation of metabolic homeostasis. Parasitic helminths are the strongest natural inducers of type 2 inflammatory responses, and several studies have revealed that helminth infections inversely correlate with metabolic syndrome. Hence, this study investigated whether helminth infections could have preventative effects on high fat diet-induced obesity. Female C57BL/6 mice were maintained on either a low fat diet (LFD, 10% fat) or a high fat diet (HFD, 60% fat) for 6 weeks after Trichinella spiralis infection. The mice were randomly divided into four groups and were fed a normal diet, LFD, LFD after T. spiralis infection (Inf + LFD), a high fat diet (HFD), or HFD after T. spiralis infection (HFD + inf). All groups were assayed for body weight, food efficiency ratio (FER), total body weight gain (g)/total food intake amount (g) fat weight, and blood biochemical parameters. Our data indicate that the HFD + inf group significantly reduced body weight gain, fat mass, total cholesterol, and FER. Analysis of immune cell composition by flow cytometry revealed that T. spiralis promoted strong decreases in proinflammatory adipose macrophages (F4/80⁺CD11c⁺) and T cells. The alterations in microbiota from fecal samples of mice were analyzed, which showed that T. spiralis infection decreased the ratio of Firmicutes to Bacteriodetes, thereby restoring the previously increased ratio of Firmicutes to Bacteriodetes in HFD-fed mice. Moreover, elimination of T. spiralis retained the protective effects in the HFD-fed obese mice whereas flubendazole (FLBZ) treatment increased levels of the families Lachnospiraceae and Ruminococcaceae. In summary, we provided novel data suggesting that helminth infection protects against obesity and the protection was closely related to M2 macrophage proliferation, an inhibiting proinflammatory response. In addition, it alters the microbiota in the gut.     

Effects of Korean white ginseng extracts on obesity in high-fat diet-induced obese mice

The present study examined the anti-obesity effect and mechanism of action of Korean white ginseng extracts (KGE) using high-fat diet (HFD)-induced obese mice. Mice were fed a low-fat diet (LFD), HFD or HFD containing 0.8 and 1.6% (w/w) KGE diet (HFD + 0.8KGE and HFD + 1.6KGE) for 8 weeks. We also examined the effects of KGE on plasma triglyceride (TG) elevation in mice administrated with oral lipid emulsion. Body weight gain and white adipose tissue (WAT) weight were significantly decreased in the HFD + 1.6KGE group, compared with the HFD group. The plasma TG levels were also significantly reduced in both HFD + 0.8KGE and HFD + 1.6KGE groups, while leptin levels were significantly decreased in only the HFD + 1.6KGE group, compared with the HFD group. The HFD + 1.6KGE group showed significantly lower mRNA levels of lipogenesis-related genes, including peroxisome proliferator-activated receptorγ2 (PPARγ2), sterol regulatory element binding protein-1c (SREBP-1c), lipoprotein lipase (LPL), fatty acid synthase (FAS) and diacylglycerol acyltransferase 1 (DGAT1), compared with the HFD group. In addition, a dose of 1000 mg/kg KGE inhibited the elevation of plasma TG levels compared with mice given the lipid emulsion alone. These results suggest that the anti-obesity effects of KGE may be elicited by regulating expression of lipogenesis-related genes in WAT and by delaying intestinal fat absorption.     

Mice Chronically Fed High-Fat Diet Have Increased Mortality and Disturbed Immune Response in Sepsis

Background

Sepsis is a potentially deadly disease that often is caused by gram-positive bacteria, in particular Staphylococcus aureus (S. aureus). As there are few effective therapies for sepsis, increased basic knowledge about factors predisposing is needed.

Methodology/Principal Findings

The purpose of this study was to study the effect of Western diet on mortality induced by intravenous S. aureus inoculation and the immune functions before and after bacterial inoculation. Here we show that C57Bl/6 mice on high-fat diet (HFD) for 8 weeks, like genetically obese Ob/Ob mice on low-fat diet (LFD), have increased mortality during S. aureus-induced sepsis compared with LFD-fed C57Bl/6 controls. Bacterial load in the kidneys 5–7 days after inoculation was increased 10-fold in HFD-fed compared with LFD-fed mice. At that time, HFD-fed mice had increased serum levels and fat mRNA expression of the immune suppressing cytokines interleukin-1 receptor antagonist (IL-1Ra) and IL-10 compared with LFD-fed mice. In addition, HFD-fed mice had increased serum levels of the pro-inflammatory IL-1β. Also, HFD-fed mice with and without infection had increased levels of macrophages in fat. The proportion and function of phagocytosing granulocytes, and the production of reactive oxygen species (ROS) by peritoneal lavage cells were decreased in HFD-fed compared with LFD-fed mice.

Conclusions

Our findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis.     

A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.     

二氢杨梅素对高脂饮食诱导的小鼠肥胖的影响及其机制

目的:观察二氢杨梅素(DHM)对高脂饮食诱导小鼠肥胖的影响,并探讨其作用机制是否与促进WAT棕色化有关。方法:60只c57bl/6j小鼠随机分为6组(n=10):①正常对照组(ND组):普通饲料喂养、②正常对照+低剂量DHM组(ND+L-DHM组):普通饲料喂养同时用低剂量DHM(125 mg/(kg·d))处理、③正常对照+高剂量DHM组(ND+H-DHM组):普通饲料喂养同时用高剂量DHM(250 mg/(kg·d))处理、④高脂饮食组(HFD):高脂饲料喂养、⑤高脂饮食+低剂量DHM组(HFD+L-DHM组):高脂饲料喂养同时用低剂量DHM处理、⑥高脂饮食+高剂量DHM组(HFD+H-DHM组):高脂饲料喂养同时用高剂量DHM处理。16周后小鼠空腹过夜,取血测空腹血糖和血脂,随后处死动物,测体长,算出Lee's指数;取肩胛下、腹股沟和附睾处脂肪组织称重后,甲醛固定、HE染色观察脂肪细胞大小,免疫组化检测解偶联蛋白1(UCP1)的表达;实验期间每4周测一次小鼠体重。结果:与ND组相比较,HFD组小鼠体重显著升高,提示肥胖小鼠模型复制成功。此外,HFD组小鼠体脂重量、脂肪细胞直径、Lee's指数和血糖显著增加、脂肪细胞UCP1的表达升高;使用L-DHM和H-DHM处理HFD小鼠后,体脂重量、脂肪细胞直径、Lee's指数和血糖等指标显著逆转,而脂肪细胞UCP1的表达升高更为显著;但L-DHM和H-DHM对正常小鼠上述指标无显著影响。结论:二氢杨梅素抑制高脂饮食诱导的小鼠肥胖,其机制可能与促进WAT棕色化有关。     

Maternal obesogenic diet combined with postnatal exposure to high-fat diet induces metabolic alterations in offspring

Maternal obesity has been shown to impact the offspring health during childhood and adult life. This study aimed to evaluate whether maternal obesity combined with postnatal exposure to an obesogenic diet could induce metabolic alterations in offspring. Female CD1 mice were fed a control diet (CD, 11.1% of energy from fat) or with a high-fat diet (HFD, 44.3% of energy from fat) for 3 months. After weaning, pups born from control and obese mothers were fed with CD or HFD for 3 months. Both mothers and offspring were weighted weekly and several blood metabolic parameters levels were evaluated. Here, we present evidence that the offspring from mothers exposed to a HFD showed increased acetylation levels of histone 3 on lysine 9 (H3K9) in the liver at postnatal Day 1, whereas the levels of acetylation of H4K16, dimethylation of H3K27, and trimethylation of H3K9 showed no change. We also observed a higher perinatal weight and increased blood cholesterol levels when compared to the offspring on postnatal Day 1 born from CD-fed mothers. When mice born from obese mothers were fed with HFD, we observed that they gained more weight, presented higher blood cholesterol levels, and abdominal adipose tissue than mice born to the same mothers but fed with CD. Collectively, our results point toward maternal obesity and HFD consumption as a risk factor for epigenetic changes in the liver of the offspring, higher perinatal weight, increased weight gain, and altered blood cholesterol levels.     

Altered food consumption in mice lacking lysophosphatidic acid receptor-1

The release of lysophosphatidic acid (LPA) by adipocytes has previously been proposed to play a role in obesity and associated pathologies such as insulin resistance and diabetes. In the present work, the sensitivity to diet-induced obesity was studied in mice lacking one of the LPA receptor subtype (LPA1R). Conversely to what was observed in wild type (WT) mice, LPA1R-KO-mice fed a high fat diet (HFD) showed no significant increase in body weight or fat mass when compared to low fat diet (LFD). In addition, in contrast to what was observed in WT mice, LPA1R-KO mice did not exhibit over-consumption of food associated with HFD. Surprisingly, when fed a LFD, LPA1R-KO mice exhibited significant higher plasma leptin concentration and higher level of adipocyte leptin mRNA than WT mice. In conclusion, LPA1R-KO mice were found to be resistant to diet-induced obesity consecutive to a resistance to fat-induced over-consumption of food that may result at least in part from alterations in leptin expression and production.     

Diet Is Critical for Prolonged Glycemic Control after Short-Term Insulin Treatment in High-Fat Diet-Induced Type 2 Diabetic Male Mice

Background

Clinical studies suggest that short-term insulin treatment in new-onset type 2 diabetes (T2DM) can promote prolonged glycemic control. The purpose of this study was to establish an animal model to examine such a “legacy” effect of early insulin therapy (EIT) in long-term glycemic control in new-onset T2DM. The objective of the study was to investigate the role of diet following onset of diabetes in the favorable outcomes of EIT.

Methodology

As such, C57BL6/J male mice were fed a high-fat diet (HFD) for 21 weeks to induce diabetes and then received 4 weeks of daily insulin glargine or sham subcutaneous injections. Subsequently, mice were either kept on the HFD or switched to a low-fat diet (LFD) for 4 additional weeks.

Principal Findings

Mice fed a HFD gained significant fat mass and displayed increased leptin levels, increasing insulin resistance (poor HOMA-IR) and worse glucose tolerance test (GTT) performance in comparison to mice fed a LFD, as expected. Insulin-treated diabetic mice but maintained on the HFD demonstrated even greater weight gain and insulin resistance compared to sham-treated mice. However, insulin-treated mice switched to the LFD exhibited a better HOMA-IR compared to those mice left on a HFD. Further, between the insulin-treated and sham control mice, in spite of similar HOMA-IR values, the insulin-treated mice switched to a LFD following insulin therapy did demonstrate significantly better HOMA-B% values than sham control and insulin-treated HFD mice.

Conclusion/Interpretation

Early insulin treatment in HFD-induced T2DM in C57BL6/J mice was only beneficial in animals that were switched to a LFD after insulin treatment which may explain why a similar legacy effect in humans is achieved clinically in only a portion of cases studied, emphasizing a vital role for diet adherence in diabetes control.     

Perinatal Overnutrition Exacerbates Adipose Tissue Inflammation Caused by High-Fat Feeding in C57BL/6J Mice

Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals. Here, we used a mouse model of early postnatal overfeeding to determine the role of neonatal nutrition in lifelong WAT inflammation and metabolic dysfunction. C57BL/6J mice were reared in small litters of 3 (SL) or normal litters of 7 pups (NL) and fed either regular chow or a 60% high fat diet (HFD) from 5 to 17 weeks. At weaning, SL mice did not develop WAT inflammation despite increased fat mass, although there was an up-regulation of WAT Arg1 and Tlr4 expression. On HFD, adult SL mice had greater inguinal fat mass compared to NL mice, however both groups showed similar increases in visceral fat depots and adipocyte hypertrophy. Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice. In addition, WAT from SL mice fed a HFD displayed greater crown-like structure formation, increased M1 macrophages, and higher cytokine gene expression. Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.     

Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway

Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory element-binding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c(-/-) mice. In contrast to control mice, in the SREBP-1c(-/-) mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway.     

敲除Nrf2促进高脂饮食诱导小鼠肝脏NF-kB的活化

目的：氧化应激和炎症反应是NASH进展的关键因素,同时二者之间存在着密切关系,而转录因子Nrf2和NF-kB分别是氧化应激和炎症信号通路的关键调控靶点,因此,研究Nrf2对高脂饮食诱导小鼠肝脏NF-kB信号通路的影响,对探讨NASH进展具有重要的意义。方法：雄性野生型（WT）和Nrf2基因敲除（Nrf2-/-）ICR小鼠各10只,随机分为WT对照组（Control）、Nrf2-/-对照组（KO）、WT高脂饮食组（HFD）和Nrf2-/-高脂饮食组（KOHFD）（n=5）。喂养8周后,观察肝脏光镜下改变,检测肝脏GSH、MDA、TNFα和IL-6水平。Western-Blot检测肝脏NF-kB蛋白表达水平,观察敲除Nrf2对肝脏NF-kB活性作用的影响。结果：1.光镜下观察,Control组与KO组小鼠肝脏结构无明显变化,HFD组小鼠肝脏呈现大片脂肪沉积和炎症细胞浸润,KOHFD组小鼠肝脏则呈现明显的大泡性变性,且炎症细胞浸润较HFD组明显加重;2.与Control组相比,KO组小鼠肝脏MDA轻度升高,GSH轻度降低,但无明显差异,而HFD组和KOHFD组小鼠肝脏MDA显著升高（P〈0.05）,GSH显著降低（P〈0.05）,且KOHFD组MDA明显高于HFD组（P〈0.05）,GSH明显低于HFD组（P〈0.05）。3.ELISA结果显示,与Control组相比,KO组小鼠肝脏TNFα和IL-6分泌轻度增加,而HFD组和KOHFD组小鼠肝脏TNFα与IL-6水平显著升高（P〈0.05）,且KOHFD组小鼠肝脏TNFα与IL-6显著高于HFD组（P〈0.05）;4.Western-Blot结果显示,Control组和KO组之间无明显差异,而KOHFD组和HFD组小鼠肝脏胞核NF-kB蛋白表达水平显著升高,且KOHFD组高于HFD组。结论：敲除Nrf2可以显著加重高脂饮食诱导的小鼠肝脏氧化应激水平,进而促进NF-kB的活化,从而为通过以Nrf2为靶点治疗NASH提供重要的实验依据。     

Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high-fat diet restriction or change to a low-fat diet

Restriction of a high-fat diet (HFD) and a change to a low-fat diet (LFD) are two interventions that were shown to promote weight loss and improve parameters of metabolic health in obesity. Examination of the biochemical and molecular responses of white adipose tissue (WAT) to these interventions has not been performed so far. Here, male C57BL/6JOlaHsd mice, harboring an intact nicotinamide nucleotide transhydrogenase gene, were fed a purified 40 energy% HFD for 14 weeks to induce obesity. Afterward, mice were divided into three dietary groups: HFD (maintained on HFD), LFD (changed to LFD with identical ingredients), and HFD-CR (restricted to 70 % of the HFD). The effects of the interventions were examined after 5 weeks. Beneficial effects were seen for both HFD-CR and LFD (compared to HFD) regarding physiological parameters (body weight and fat mass) and metabolic parameters, including circulating insulin and leptin levels. Macrophage infiltration in WAT was reduced by both interventions, although more effectively by HFD-CR. Strikingly, molecular parameters in WAT differed between HFD-CR and LFD, with increased activation of mitochondrial carbohydrate and fat metabolism in HFD-CR mice. Our results confirm that restriction of the amount of dietary intake and reduction in the dietary energy content are both effective in inducing weight loss. The larger decrease in WAT inflammation and increase in mitochondrial carbohydrate metabolism may be due to a larger degree of energy restriction in HFD-CR, but could also be due to superior effectiveness of dietary restriction in weight loss strategies.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-014-0391-9) contains supplementary material, which is available to authorized users.     

Alterations and structural resilience of the gut microbiota under dietary fat perturbations

Disequilibrium of the gut microbiota by dietary fat has been implicated in the incidence of overweight or obesity. However, it remains to be elucidated whether dietary fat perturbations in early life have long-lasting impacts on the gut microbiota and to what extent unbalanced diet-induced alterations in childhood are reversible. Accordingly, three groups of 1-day-old hens were used. They were fed with a low-fat diet (LFD), basal diet (BD) and high-fat diet (HFD), respectively, for 6 weeks and then switched to the same normal diets (NDs) for another 19 weeks. At week 6, hens in the LFD and HFD groups were found to have higher body weight, plasma glucose, total cholesterol, triglycerides and low-density lipoprotein cholesterol levels than their counterparts in the BD group, whereas upon switching to NDs, the metabolic deteriorations observed during the LFD consumption were alleviated. Principal component analysis revealed a shift of the gut microbiota structure in the LFD and HFD groups away from that of the BD group at week 6, while the gut microbiota structure of the LFD group was moved back to that of the BD group after reverting to NDs. Additionally, abnormal alterations of obesity-related phylotypes were observed in the LFD and HFD groups, whereas the abundance of these phylotypes in the LFD group was almost reverted to the BD levels over time. Collectively, dietary fat perturbations in early life have long-term impacts on hosts, and the structural resilience of the gut microbiota in hens fed with HFD was lower than that in their LFD counterparts.     

The influence of sex and strain on trace element dysregulation in the brain due to diet-induced obesity

BackgroundThe objective of this study was to identify interaction effects between diet, sex, and strain on trace element dysregulation and gene expression alterations due to diet-induced obesity (DIO) in the hippocampus, striatum, and midbrain.MethodsMale and female C57BL/6 J (B6 J) and DBA/2 J (D2 J) mice were fed either a low fat (10 % kcal) diet (LFD) or high fat (60 % kcal) diet (HFD) for 16 weeks, then assessed for trace element concentrations and gene expression patterns in the brain.ResultsIn the hippocampus, zinc was significantly increased by 48 % in D2 J males but decreased by 44 % in D2 J females, and divalent metal transporter 1 was substantially upregulated in B6 J males due to DIO. In the striatum, iron was significantly elevated in B6 J female mice, and ceruloplasmin was significantly upregulated in D2 J female mice due to DIO. In the midbrain, D2 J males fed a HFD had a 48 % reduction in Cu compared to the LFD group, and D2 J females had a 37 % reduction in Cu compared to the control group.ConclusionsThe alteration of trace element homeostasis and gene expression due to DIO was brain-region dependent and was highly influenced by sex and strain. A significant three-way interaction between diet, sex, and strain was discovered for zinc in the hippocampus (for mice fed a HFD, zinc increased in male D2 Js, decreased in female D2 Js, and had no effect in B6 J mice). A significant diet by sex interaction was observed for iron in the striatum (iron increased only in female mice fed a HFD). A main effect of decreased copper in the midbrain was found for the D2 J strain fed a HFD. These results emphasize the importance of considering sex and genetics as biological factors when investigating potential associations between DIO and neurodegenerative disease.