Intermittent Fasting Alters Serum Exosomes in Middle-Aged Male Mice on Long-Term High-Fat Diet

Abstract Objectives Extracellular vesicles (EVs), especially exosomes, have emerged as a critical regulator of intercellular and inter-organ communications. Dysregulation of exosome secretion and exosomal cargo composition has been associated with metabolic diseases. The objective of this study was to determine the effect of intermittent fasting (IF) on the size profile and cargoes of exosomes in diet-induced obesity. Methods Female and male mice (8–10 weeks old) were fed a high-fat diet (HFD) for 18 weeks prior to being placed either in an ad libitum feeding group (HFD-AL) or an IF feeding group (HFD-IF) for an additional 10 weeks. Mice on the normal chow ad libitum (NC-AL) for 28 weeks served as control. The IF group had food available for 10 hours and fasted for 14 hours daily. Serum EVs measured using Nanoparticle Tracking Analysis. Results HFD-AL mice had an increasing trend in mean diameter of serum EVs by 24 nm (P = 0.30) compared to the NC-AL mice. The IF caused a significant decrease in mean diameter of serum EVs by 47.9 nm (P < 0.03) when compared to the HFD-AL mice. However, neither HFD nor IF altered the overall particle amount per mL of serum when compared to NC-AL. The HFD-AL mice had a decreasing trend in the population of small-size EVs but an increase in large-size EVs compared to the NC-AL mice. Mice on long-term HFD with IF had a significant increase in the total amount of small EVs/exosomes (50–100 nm in size) per unit of serum, but a decrease in the amount of large EVs (250–500 nm in size). Moreover, the mean population (particles/ml) of small EVs/exosomes were increased in the HFD-IF mice by an average of 38% (P < 0.03), whereas the population of large-size micro-vesicles (250–300 nm in size) were decreased by an average of 4% (P < 0.01) when compared to the HFD-AL mice. In addition to exosome alterations, the weekly weigh-in differences were significantly higher in the HFD-IF mice compared to the HFD-AL mice (P < 0.02). Lastly, we found that IF could prevent the whitening of brown adipose tissue (BAT) and liver micro-vesicular steatosis induced by a long-term HFD. Conclusions IF significantly alters the profile of serum EVs, which may serve as an important mechanism for the metabolic benefits of IF such as preventing the whitening of BAT and liver micro-vesicular steatosis in obesity. Funding Sources This work was supported by the General Mills Foundation Chair in Genomics for Healthful Foods to X.C.

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The effect of calorie intake, fasting, and dietary composition on metabolic health and gut microbiota in mice

BMC Biology ◽

10.1186/s12915-021-00987-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ziyi Zhang ◽

Xiaoyu Chen ◽

Yuh Jiun Loh ◽

Xin Yang ◽

Chenhong Zhang

Keyword(s):

Gut Microbiota ◽

High Fat Diet ◽

Metabolic Health ◽

Metabolic Phenotype ◽

Intermittent Fasting ◽

High Fat ◽

Eating Pattern ◽

Positive Effects ◽

Normal Chow ◽

Ad Libitum

Abstract Background Calorie restriction (CR) and intermittent fasting (IF) can promote metabolic health through a process that is partially mediated by gut microbiota modulation. To compare the effects of CR and IF with different dietary structures on metabolic health and the gut microbiota, we performed an experiment in which mice were subjected to a CR or IF regimen and an additional IF control (IFCtrl) group whose total energy intake was not different from that of the CR group was included. Each regimen was included for normal chow and high-fat diet. Results We showed that in normal-chow mice, the IFCtrl regimen had similar positive effects on glucose and lipid metabolism as the CR regimen, but the IF regimen showed almost no influence compared to the outcomes observed in the ad libitum group. IF also resulted in improvements, but the effects were less marked than those associate with CR and IFCtrl when the mice were fed a high-fat diet. Moreover, CR created a stable and unique gut microbial community, while the gut microbiota shaped by IF exhibited dynamic changes in fasting-refeeding cycles. At the end of each cycle, the gut microbiota of the IFCtrl mice was similar to that of the CR mice, and the gut microbiota of the IF mice was similar to that of the ad libitum group. When the abundance of Lactobacillus murinus OTU2 was high, the corresponding metabolic phenotype was improved regardless of eating pattern and dietary structure, which might be one of the key bacterial groups in the gut microbiota that is positively correlated with metabolic amelioration. Conclusion There are interactions among the amount of food intake, the diet structure, and the fasting time on metabolic health. The structure and composition of gut microbiota modified by dietary regimens might contribute to the beneficial effects on the host metabolism.

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Metabolic Flexibility: Interplay of Diet Composition and Intermittent Fasting on Healthspan (P08-053-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p08-053-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Sarah Wong ◽

Rafael de Cabo ◽

Michel Bernier ◽

Alberto Diaz-Ruiz ◽

Tyler Rhinesmith ◽

...

Keyword(s):

Insulin Sensitivity ◽

High Fat Diet ◽

Diet Composition ◽

Intermittent Fasting ◽

Metabolic Flexibility ◽

Standard Diet ◽

High Fat ◽

High Fat Diets ◽

Ad Libitum ◽

Fat Diets

Abstract Objectives 4:10 periodic fasting schedule is proposed to improve biomarkers of healthspan through metabolic flexibility in mice on both standard and high fat diets. Methods Our study adopted the 4:10 fasting schedule using the fasting-mimicking diet (FMD) as our model. FMD is a plant-based, low-protein, and low-sugar diet regime implemented for four days every two-week cycle. Its regenerative effect is observed in the refeeding phase following starvation, allowing for the breakdown of cells via increased autophagy. In comparison to stricter fasting regimes such as intermittent fasting, chronic caloric restriction, and periodic fasting, FMD is well-tolerated in the clinical setting. 74 12-month old C57BL/6 mice were randomized into two diet groups: standard diet or high-fat diet. For 4 days out of every fourteen days, the mice were severely caloric restricted and refed with ad-libitum of either standard or high fat diets for the remaining 10 days, matching the controls who were fixed on the ad-libitum diet. The 4:10 fasting schedule was repeated 11 times before the mice were sacrificed. To measure metabolic flexibility, metabolic cages, ELISA, and glucose meters were used. Results Body weight and composition, metabolic flexibility, and insulin sensitivity indicate differences between fasting on diet composition. Not only did those on the fasting high-fat diet (FHFD) remain overweight, identical to their HFD controls, insulin sensitivity was also attenuated in FHFD groups. Fasting standard diet (FSD) had a reduction of 5% in body weight and 15% in body fat. Carbohydrate and lipid metabolism differences indicated by the respiratory exchange ratio as well as motor function performance differences further support the positive impact of fasting on SD groups, not HFD groups. Characteristic of positive healthspan biomarkers, reduced leptin and improved insulin sensitivity was observed with FSD, not FHFD. Conclusions We found that while the FMD schedule improved healthspan as indicated by biomarkers of healthy aging for mice on the standard diet, it could not counteract the negative health effects of the obesogenic diet. These results demonstrate the importance of not only time of feeding but also diet composition in respect to healthspan. Funding Sources National Institute on Aging (NIA) – National Institutes of Health (NIH).

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Patchouli Alcohol from Pogostemon Cablin Prevents Development of Obesity and Improves Glucose Tolerance in High Fat Diet-induced Obese Mice (P06-107-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-107-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Jihye Lee ◽

Seong-Ho Lee

Keyword(s):

Body Weight ◽

Glucose Tolerance ◽

High Fat Diet ◽

Oral Glucose ◽

Male Mice ◽

Fat Pad ◽

High Fat ◽

Patchouli Alcohol ◽

Brown Adipose ◽

Pogostemon Cablin

Abstract Objectives Patchouli alcohol is a sesquiterpene alcohol found in Pogostemon cablin. Recently, we observed that patchouli alcohol reduced lipid accumulation in differentiated 3T3-L1 adipocytes and increased glucose uptake in differentiated C2C12 myocytes. This study was designed to investigate anti-obese and anti-diabetic activities of patchouli alcohol using high fat diet-induced obese mouse model. Methods Forty-eight 5-week old C57BL/6 J male mice were assigned into four groups and fed with 1) normal diet (control), 2) high fat diet, 3) high fat diet with gavaging 25 mg of patchouli alcohol/kg body weight and 4) high fat diet with gavaging 50 mg of patchouli alcohol/kg body weight. High fat diet or control diets were provided to each treatment group for four weeks and then different doses of patchouli alcohol (0, 25 or 50 mg/kg body weight) was orally administered for following 8 weeks with the diet. At age of week 17, all animals were sacrificed, fat tissues were collected, and tissue weight was measured. In addition, twenty C57BL/6 J male mice were assigned into the same treatment groups above. At the end of the 8 weeks (age of week 17), the mice were fasted for 12 h and the oral glucose tolerance test was performed after intraperitoneal injection of 2 g of anhydrous glucose/kg body weight. The blood was collected from tail at 0, 15, 30, 90 and 120 min after injection and blood glucose level was analyzed using glucose meter. Results Treatment of patchouli alcohol (50 mg/kg body weight) significantly reduced body weight and accumulation of body fat pads which was highly induced by feeding of high fat diet. An analysis of individual fat pad weights (expressed as mg weight of fat pad/g body weight) revealed a significant decrease of epididymal and retroperitoneal fat pad in patchouli alcohol-treated mice whereas brown adipose tissue were not significantly altered. And, slightly improved glucose tolerance was observed at 90 and 120 minutes after glucose injection in mice treated with patchouli alcohol (50 mg/kg body weight) compared to those fed with high fat diet alone. Conclusions We propose a potential use of patchouli alcohol as an anti-obesity compound in obese population. Funding Sources NIFA Hatch grant. Supporting Tables, Images and/or Graphs

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Loss of Sirt6 in adipocytes impairs the ability of adipose tissue to adapt to intermittent fasting

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00664-1 ◽

2021 ◽

Vol 53 (9) ◽

pp. 1298-1306

Author(s):

Dandan Wu ◽

In Hyuk Bang ◽

Byung-Hyun Park ◽

Eun Ju Bae

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Intermittent Fasting ◽

Metabolic Profiles ◽

Wild Type ◽

High Fat ◽

Ad Libitum ◽

The Relationship ◽

Tissue Browning

AbstractIntermittent fasting (IF) is gaining popularity for its effectiveness in improving overall health, including its effectiveness in achieving weight loss and euglycemia. The molecular mechanisms of IF, however, are not well understood. This study investigated the relationship between adipocyte sirtuin 6 (Sirt6) and the metabolic benefits of IF. Adipocyte-specific Sirt6-knockout (aS6KO) mice and wild-type littermates were fed a high-fat diet (HFD) ad libitum for four weeks and then subjected to 12 weeks on a 2:1 IF regimen consisting of two days of feeding followed by one day of fasting. Compared with wild-type mice, aS6KO mice subjected to HFD + IF exhibited a diminished response, as reflected by their glucose and insulin intolerance, reduced energy expenditure and adipose tissue browning, and increased inflammation of white adipose tissue. Sirt6 deficiency in hepatocytes or in myeloid cells did not impair adaptation to IF. Finally, the results indicated that the impaired adipose tissue browning and reduced expression of UCP1 in aS6KO mice were accompanied by downregulation of p38 MAPK/ATF2 signaling. Our findings indicate that Sirt6 in adipocytes is critical to obtaining the improved glucose metabolism and metabolic profiles conferred by IF and that maintaining high levels of Sirt6 in adipocytes may mimic the health benefits of IF.

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Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00505.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. E1236-E1243 ◽

Cited By ~ 81

Author(s):

Elena Velkoska ◽

Timothy J. Cole ◽

Margaret J. Morris

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Adipose Tissue ◽

Neuropeptide Y ◽

Litter Size ◽

High Fat Diet ◽

Dietary Intervention ◽

High Fat ◽

Brown Adipose

Early life nutrition impacts on subsequent risk of obesity and hypertension. Several brain chemicals responsible for both feeding and cardiovascular regulation are altered in obesity. We examined effects of early postnatal overnutrition on blood pressure, brain neuropeptide Y (NPY), and adiposity markers. Rat pup litters were adjusted to either 3 or 12 male animals (overnutrition and control, respectively) on day 1 of life. After weaning, rats were given either a palatable high-fat diet or standard chow. Smaller litter pups were significantly heavier by 17 days of age. By 16 wk, the effect of litter size was masked by that of diet, postweaning. Small and normal litter animals fed a high-fat diet had similar increases in body weight, plasma insulin, leptin, and adiponectin concentrations, leptin mRNA, and fat masses relative to chow-fed animals. An increase in 11β-hydroxysteroid dehydrogenase-1 mRNA in white adipose tissue, and a decrease in uncoupling protein-1 mRNA in brown adipose tissue in both small litter groups at 16 wk of age, may represent a programming effect of the altered litter size. NPY concentration in the paraventricular nucleus of the hypothalamus was reduced in high fat-fed groups. Blood pressure was significantly elevated at 13 wk in high-fat-fed animals. This study demonstrates that overnourishment during early postnatal development leads to profound changes in body weight at weaning, which tended to abate with maturation. Thus the effects of long-term dietary intervention postweaning can override those of litter size-induced obesity.

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Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet–induced obesity and its metabolic complications in male mice

Molecular Metabolism ◽

10.1016/j.molmet.2019.10.010 ◽

2020 ◽

Vol 31 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Almudena Gomez-Hernandez ◽

Andrea R. Lopez-Pastor ◽

Carlota Rubio-Longas ◽

Patrik Majewski ◽

Nuria Beneit ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Male Mice ◽

High Fat ◽

Metabolic Complications ◽

Diet Induced Obesity ◽

Brown Adipose

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Intermittent Fasting Improves Glucose Tolerance and Promotes Adipose Tissue Remodeling in Male Mice Fed a High-Fat Diet

Endocrinology ◽

10.1210/en.2018-00701 ◽

2018 ◽

Vol 160 (1) ◽

pp. 169-180 ◽

Cited By ~ 17

Author(s):

Bo Liu ◽

Amanda J Page ◽

George Hatzinikolas ◽

Miaoxin Chen ◽

Gary A Wittert ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

High Fat Diet ◽

Tissue Remodeling ◽

Intermittent Fasting ◽

Male Mice ◽

High Fat ◽

Adipose Tissue Remodeling

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Engineered human brown adipocyte microtissues improved glucose and insulin homeostasis in high fat diet-induced obese and diabetic mice

10.1101/2021.10.11.463939 ◽

2021 ◽

Author(s):

Ou Wang ◽

Li Han ◽

Haishuang Lin ◽

Mingmei Tian ◽

Shuyang Zhang ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

High Fat Diet ◽

Diabetic Mice ◽

High Fat ◽

Brown Adipose ◽

Insulin Homeostasis ◽

Human And Mouse

AbstractA large population of people is affected by obesity (OB) and its associated type 2 diabetes mellitus(T2DM). There are currently no safe and long-lasting anti-OB/T2DM therapies. Clinical data and preclinical transplantation studies show that transplanting metabolically active brown adipose tissue (BAT) is a promising approach to prevent and treat OB and its associated metabolic and cardiovascular diseases. However, most transplantation studies used mouse BAT, and it is uncertain whether the therapeutic effect would be applied to human BAT since human and mouse BATs have distinct differences. Here, we report the fabrication of three-dimensional (3D) human brown adipose microtissues, their survival and safety, and their capability to improve glucose and insulin homeostasis and manage body weight gain in high-fat diet (HFD)-induced OB and diabetic mice.Methods3D BA microtissues were fabricated and transplanted into the kidney capsule of Rag1-/- mice. HFD was initiated to induce OB 18 days after transplantation. A low dose of streptozotocin (STZ) was administrated after three month’s HFD to induce diabetes. The body weight, fat and lean mass, plasma glucose level, glucose tolerance and insulin sensitivity were recorded regularly. In addition, the levels of human and mouse adipokines in the serum were measured, and various tissues were harvested for histological and immunostaining analyses.ResultsWe showed that 3D culture promoted BA differentiation and uncoupling protein-1 (UCP-1) protein expression, and the microtissue size significantly influenced the differentiation efficiency and UCP-1 protein level. The optimal microtissue diameter was about 100 µm. Engineered 3D BA microtissues survived for the long term with angiogenesis and innervation, alleviated body weight and fat gain, and significantly improved glucose tolerance and insulin sensitivity. They protected the endogenous BAT from whitening and reduced mouse white adipose tissue (WAT) hypertrophy and liver steatosis. In addition, the microtissues secreted soluble factors and modulated the expression of mouse adipokines. We also showed that scaling up the microtissue production could be achieved using the 3D suspension culture or a 3D thermoreversible hydrogel matrix. Further, these microtissues can be preserved at room temperature for 24 hours or be cryopreserved for the long term without significantly sacrificing cell viability.ConclusionOur study showed that 3D BA microtissues could be fabricated at large scales, cryopreserved for the long term, and delivered via injection. BAs in the microtissues had higher purity, and higher UCP-1 protein expression than BAs prepared via 2D culture. In addition, 3D BA microtissues had good in vivo survival and tissue integration, and had no uncontrolled tissue overgrowth. Furthermore, they showed good efficacy in preventing OB and T2DM with a very low dosage compared to literature studies. Thus, our results show engineered 3D BA microtissues are promising anti-OB/T2DM therapeutics. They have considerable advantages over dissociated BAs or BAPs for future clinical applications in terms of product scalability, storage, purity, quality, and in vivo safety, dosage, survival, integration, and efficacy.

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Intermittent Fasting Ameliorated High-Fat Diet-Induced Memory Impairment in Rats via Reducing Oxidative Stress and Glial Fibrillary Acidic Protein Expression in Brain

Nutrients ◽

10.3390/nu13010010 ◽

2020 ◽

Vol 13 (1) ◽

pp. 10

Author(s):

Suzan M. Hazzaa ◽

Mabrouk A. Abd Eldaim ◽

Amira A. Fouda ◽

Asmaa Shams El Dein Mohamed ◽

Mohamed Mohamed Soliman ◽

...

Keyword(s):

Body Weight ◽

Glial Fibrillary Acidic Protein ◽

Brain Tissue ◽

High Fat Diet ◽

Serum Lipids ◽

Memory Performance ◽

Granular Cell ◽

Intermittent Fasting ◽

High Fat ◽

Cell Layers

Intermittent fasting (IF) plays an important role in the protection against metabolic syndrome-induced memory defects. This study aimed to assess the protective effects of both prophylactic and curative IF against high-fat diet (HFD)-induced memory defects in rats. The control group received a normal diet; the second group received a HFD; the third group was fed a HFD for 12 weeks and subjected to IF during the last four weeks (curative IF); the fourth group was fed a HFD and subjected to IF simultaneously (prophylactic IF). A high-fat diet significantly increased body weight, serum lipids levels, malondialdehyde (MDA) concentration, glial fibrillary acidic protein (GFAP) and H score in brain tissue and altered memory performance. In addition, it significantly decreased reduced glutathione (GSH) concentration in brain tissue and viability and thickness of pyramidal and hippocampus granular cell layers. However, both types of IF significantly decreased body weight, serum lipids, GFAP protein expression and H score and MDA concentration in brain tissue, and improved memory performance, while it significantly increased GSH concentration in brain tissue, viability, and thickness of pyramidal and granular cell layers of the hippocampus. This study indicated that IF ameliorated HFD-induced memory disturbance and brain tissue damage and the prophylactic IF was more potent than curative IF.

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The beneficial effects of Lactobacillus fermented black barley on high fat diet-induced fatty liver in rats

Food & Function ◽

10.1039/d1fo00290b ◽

2021 ◽

Author(s):

Qi Guan ◽

Xinwen Ding ◽

Lingyue Zhong ◽

Chuang Zhu ◽

Pan Nie ◽

...

Keyword(s):

Fatty Liver ◽

High Fat Diet ◽

Metabolic Disorders ◽

High Fat ◽

Beneficial Effects ◽

Phytochemical Composition

Long term high-fat diet (HF) can cause metabolic disorders, which might induce fatty liver. Fermented whole cereal food exhibit healthy potential due to their unique phytochemical composition and probiotics. In...

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