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The dangers of high fat diet(mouse model)
[2009] Mice Chronically Fed High-Fat Diet Have Increased Mortality and Disturbed Immune Response in Sepsis
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007605
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.
Our findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis.
Sepsis is often a deadly disease with increasing incidence worldwide [1]. Gram-positive bacteria, in particular Staphylococcus aureus (S. aureus), are a predominant and increasing cause of sepsis [1], [2]. Sepsis consists of a hyperinflammatory state during the first few days followed by a prolonged hypoimmune state during which death often occurs [3], [4]. At present, there are few treatments for sepsis, besides antibiotics [3], [5], and antibiotic resistance is increasing globally [6]. In addition, few treatments for sepsis developed in experimental animals have resulted in clinical use [4], [5]. Therefore, increased basic knowledge about factors predisposing to this deadly disease is urgently needed.
Like sepsis, obesity is increasing epidemically and this is believed to be due to the consumption of energy dense food, such as fat rich diets, combined with polygenetically determined susceptibility [7], [8]. There may be interactions between the immune system and body fat metabolism. The adipose tissue of obese and insulin resistant individuals can produce and release cytokines, first shown by Hotamisligil & Spiegelman for tumor necrosis factor (TNF)-α [9]. More recently, it has been suggested that macrophages accumulating in fat [10], [11] contribute to obesity-induced cytokine release and low-grade inflammation, which in turn could cause insulin resistance and atherosclerosis in obese subjects [10]–[12]. Considerably less is known about how this condition may influence the main task of the immune system, to combat infections. Clinical findings indicate that obesity is associated with increased susceptibility to infections [13]. However, this association could be due to multiple factors, e.g. longer surgery and hospitalization time of obese patients, with increased risk for nosocomial infections [13]. Alternatively, obesity could be secondary to immune defects. Previous studies have shown that innate immune dysfunction, associated with absence of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, IL-1RI, and IL-18, leads to obesity [14]–[19]. Conversely, ingestion of energy dense food and obesity may suppress the immune response. In clinical materials it is very difficult to clarify the possible causality as well as cellular and molecular links between obesity and potential defective immune function.
In the present study we used an animal model to determine whether ingestion of fat with resulting obesity can affect the capacity of the immune system to resist bacterial sepsis. We studied chronic high-fat diet (HFD) fed mice, which have been shown to reflect common forms of clinical obesity and obesity related disease that depend on multiple genetic factors as well as diet [20], [21]. The bacterial challenge model used in this study was injection of S. aureus, a common cause of sepsis in humans.
To investigate if the increased mortality in HFD-fed mice was due to under- or over-reactivity of the immune system, we measured bacterial load in blood and kidneys on day 1 and in kidneys on days 5–7 after staphylococcal inoculation. There was no difference in bacterial load in either blood or kidneys 1 day after inoculation (Fig. S2). However, 5–7 days after inoculation there was a 10-fold increase in the number of staphylococcal CFU in the kidneys from HFD-fed mice, compared with LFD-fed mice (P = 0.001, Fig. 1B).
Increased cytokines in serum of infected HFD-fed mice
We measured several serum cytokines in uninfected and infected mice. In uninfected mice the only difference was seen in the levels of the anti-inflammatory cytokine IL-1Ra, which were increased in HFD-fed mice (169 (range: 33–1111) and 1587 (range: 84–32245) pg ml−1, for LFD- vs. HFD-fed mice, P<0.001, ANCOVA on log data with experiment as covariate, data from 4 different experiments, n = 28+26). Infected HFD-fed mice had 4.9-fold increased levels of IL-1Ra (P<0.001) and also 4.7-fold increased levels of another anti-inflammatory cytokine, IL-10 (P<0.001, Fig. 2A and B). IL-6 has pro-inflammatory functions, but has also been found to have anti-inflammatory effects [29], [30]. This cytokine was increased in four HFD-fed mice, but overall not significantly (Fig. 2C). Among the pro-inflammatory cytokines measured, IL-1β was increased (P = 0.02) and there was a tendency for increased TNF-α in HFD-fed mice, compared with LFD-fed mice (Fig. 2D and E).
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HFD-fed mice had increased delayed mortality in S. aureus-induced sepsis from about one week after bacterial inoculation. Acute administration of HFD at the time of inoculation did not lead to increased mortality. This indicates that the increased mortality in HFD-fed mice is due to chronic effects of the diet, for example obesity, rather than short-term effects of the HFD. The finding that genetically-induced obese Ob/Ob mice given LFD also display increased mortality supports this notion. The increased mortality appears to be due to an under reactivity of the innate immune system, as an increased bacterial load was found in the kidneys of HFD-fed mice. The reason for this disturbed innate immune function is unknown, but we observed several possible mechanisms. The anti-inflammatory cytokine IL-1Ra was increased in serum and fat in both uninfected and infected HFD-fed mice compared with LFD-fed mice. The other measured anti-inflammatory cytokine, IL-10, was increased in serum in infected HFD-fed mice, and in fat in uninfected and infected HFD-fed mice. However, the serum levels of the pro-inflammatory cytokine IL-1β were also increased, while the levels of the TNF-α and IL-6 tended to be increased in HFD-fed mice. In summary, both pro-inflammatory and anti-inflammatory cytokines were enhanced in mice given HFD. In addition, both the proportion and function of granulocytes were decreased in uninfected HFD-fed mice, and the ROS production by phagocytosing cells was greatly decreased in infected HFD-fed mice. Therefore, several immune functions were disturbed in chronically HFD-fed mice.
The finding that the HFD-fed mice had some signs of decreased immune response during infection was surprising, as data in the literature clearly show that uninfected HFD-fed mice have a chronic inflammation, i.e. stimulated immune functions [9]–[12], [31], [32].
Although the immune system of obese individuals is thus activated already at the time of infection, our results show that this chronic activation does not facilitate immune system activation and pathogen clearance during infection.
If anything, chronic inflammation seems associated with impaired effectiveness of the immune system.
In line with our findings, the autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus are associated with increased risk of acquiring infections, an event seemingly independent of immunosuppressive treatments [33], [34].
Obesity has been shown to up-regulate production of both pro- and anti-inflammatory cytokines, from adipocytes and/or fat infiltrating macrophages [9]–[12], [35]–[37], as consistent with the present findings in uninfected HFD-fed mice. The anti-inflammatory cytokines IL-1Ra and IL-10 were both markedly up-regulated in fat and serum in HFD-fed mice on day 5–7 after bacterial challenge. At this time point HFD-fed mice have increased bacterial load and their mortality starts to increase. IL-1β was the only measured pro-inflammatory cytokine that then was higher in serum of HFD-fed mice, although there was a tendency for increased TNF-α and IL-6. The relatively large up-regulation of anti- versus pro-inflammatory cytokines in serum may be important for the decreased survival of HFD-fed mice in this study. The mortality in clinical sepsis often occurs days to weeks after the first clinical event and is associated with a shift toward an immunosuppressive state [3], [4]. In fact, it has been shown that IL-1Ra treatment before inoculation enhances mortality in experimental sepsis [38] and IL-10 neutralization has also been shown to enhance survival to sepsis [39].
In the present study we confirm earlier findings that uninfected HFD-fed mice accumulate macrophages in fat [10], [11]. They also have higher monocyte/macrophage proportion in blood and spleen. When infected, HFD-fed mice still have an accumulation of macrophages in their fat. However, infected HFD-fed mice had a lower monocyte proportion in blood, and the proportion of phagocytosing monocytes was decreased in uninfected HFD-fed mice. At present, it is unclear to what extent decreased macrophage function contributes to decreased immune response to S. aureus in HFD-fed mice.
We observed several signs of decreased granulocyte/neutrophil efficacy in HFD-fed mice, including decreased proportion in blood of neutrophils, decreased proportion of phagocytosing granulocytes, and fewer ingested bacteria per granulocyte in uninfected HFD-fed mice.
There was also a marked decrease in ROS production by phagocytic cells in infected HFD-fed mice.
Neutrophilic dysfunction clearly contributes to increased bacterial growth and increased mortality [40]–[42], reasonably also in HFD-fed mice. Indeed, neutrophils, the major subpopulation of granulocytes, are often first to migrate into tissues in response to invading pathogens and to attack bacteria in the blood circulation [43], [44]. Neutrophilic depletion in mice leads to severely increased mortality in S. aureus-induced sepsis [22]. Furthermore, most patients with congenital neutropenia, also known as Kostmann syndrome, die from bacterial infections in early childhood, unless properly treated [45]. These findings emphasize the importance of neutrophils in the early clearance of bacteria. Interestingly, there are indications that neutrophil function and ROS production is of importance not only to overcome an infection, but also for the subsequent resolution of the inflammation [43], [46], [47]. The role of neutrophil function for HFD-associated inflammation remains to be further investigated.
In line with our study, Leeman and coworkers recently reported that HFD-induced obesity aggravates a local infection, the periodontitis caused by Porphyromonas gingivalis [48].
These results are of interest as it is well established that periodontitis is associated with obesity [49]. Taken together with our findings it appears that the immune response in general is decreased by HFD both with regard to low-grade chronic local infection and acute life-threatening generalized infection.
A limitation with the use of HFD-fed mice is that it is difficult to determine whether it is the diet itself, or secondary causes thereof, such as obesity or blood fat disturbances that influence the immune system. For example, Kopf et al found that several immune related parameters change in Apoe−/− mice given high fat high cholesterol diet, as a model of dyslipidemia [50]. In this study we fed C57BL/6 mice a HFD with a 30-time lower cholesterol content, that do not cause major dyslipidemia in this strain [51]. Thus blood fat disturbances are an unlikely mediator of immune suppression in our HFD-fed mice. Differences in diet may also affect immune functions indirectly via effects on bacterial load instead of vice versa. Furthermore, there is always a possibility of species differences between mice and humans. For instance, the proportion of neutrophils was decreased by HFD in uninfected mice in this study, while neutrophils in blood seem to be higher in obese humans [52].
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In the present study we found increased mortality not only in obese HFD-fed mice, but also in genetically obese Ob/Ob mice that had not been given HFD. Complete lack of leptin activity is associated with immune deficiencies in both mice and humans, e.g. suppression of T-cells [53], [54]. Therefore, it is possible that the reason for increased mortality differ between Ob/Ob and HFD-fed mice. This is supported by the fact that IL-1Ra and IL-10 response after LPS exposure is decreased in Ob/Ob mice [55], although we observed higher levels of IL-1Ra and IL-10 in HFD-fed obese mice in the present study. It should be noted that complete lack of leptin activity is a very rare cause of severe obesity in humans, while HFD-fed mice is generally accepted as a good model for the common clinical obesity due to the combined effect of high caloric density diet and multigenic predisposition [20], [21].
Like obesity, sepsis and especially that caused by S. aureus is increasing worldwide [1], [2] and it is therefore urgent to understand basic mechanisms and find better treatments for this condition. The present study shows for the first time that HFD-fed mice, despite their well known low-grade inflammation, have increased mortality and bacterial proliferation in connection to sepsis. These effects occurred several days after bacterial challenge, i.e. at a time when mortality often occurs in clinical sepsis, not seldom because of hypoinflammation [3], [4].
The HFD-fed mice had disturbed innate immune functions, as indicated by increased levels of immune suppressing and immune stimulating cytokines and decreased granulocyte function.
Based on successful animal studies, sepsis treatment in clinical trials has often sought to decrease an early overactive immune response, but these drugs have been largely ineffective [3]–[5]. Experimental studies have usually been performed on lean young animals, while patients with sepsis on average are 55–60 years old and often have several symptoms of the metabolic syndrome [1]. We suggest that experimental sepsis studies should be conducted in models that are metabolically more similar to the clinical situation.
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(C) Percentage of phagocytosing monocytes in uninfected low fat diet and high fat diet fed mice. Welch's t-test. (D) Ingested bacteria per monocyte in uninfected low fat diet and high fat diet fed mice.
Short-term high-fat diet affects macrophages inflammatory response, early signs of a long-term problem
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1984-82502019000100548
Obesity is a chronic inflammatory disease that affects millions of people worldwide. Most studies observe the effects of a high-fat diet (HFD) in 10-12 weeks. This work investigated the effects induced by a HFD administered for 6 weeks on the nutritional status of mice and some aspects of the inflammatory response in mouse peritoneal macrophages.
A HFD was associated with increased cholesterol, insulin resistance, C-reactive protein (CRP), leptin, and serum resistin levels. Lipopolysaccharide (LPS)- stimulated adipocyte cultures of animals subjected to a HFD showed increased production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). However, peritoneal macrophages of the HFD group showed no changes in the levels of these cytokines. LPS-stimulated peritoneal macrophages from HFD-treated animals showed a reduction in mRNA expression of TNF-α and IL-6, as well as a decrease in expression of the transcription factor nuclear factor-kappa B (NF-kB).
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Metabolic disorders associated with high fat diet. The diagram shows the processes affected by high fat diet. Abbreviations: NF-KB, nuclear factor kappa B; TNF, tumor necrosis factor; IL-6, Interleukin-6; LPS, lipopolysaccharide.
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Our study suggests that consumption of a HFD by mice, even in the short term, decreases the ability of peritoneal macrophages to develop an adequate inflammatory response to a bacterial component[endotoxin].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931384/
Role of Saturated Fatty Acids and Gut-Generated LPS as TLR4 Ligands
Are saturated fatty acids actual ligands of TLR4?
SFA activation of TLR4 is an attractive link between obesity, insulin resistance, and inflammation, as cellular exposure to SFA greatly increases in the obese state. SFA are acyl components of LPS, activate TLR4 in vitro, and bind directly to TLR4/MD2/LPS crystal structures, although in an orientation that would probably rely on their presentation in an acylated form [35, 36]. Recent studies document endotoxin contamination of experimental reagents (such as bovine serum albumin, BSA) which would generate false-positive experimental results regarding the TLR4 agonistic effects of SFA [37–39]. LPS contamination is pervasive and LPS levels can only be assayed indirectly [31, 40]. Nonetheless, many publications document activation of TLR4 via SFA and many of these include samples that control for possible endotoxin contamination, for example, studies wherein BSA-complexed SFA treatments activate TLR4 effects but BSA alone and BSA-complexed monounsaturated fatty acid treatments do not. Extensive literature suggests that high-fat diet-augmented postprandial endotoxemia is a possible mode by which dietary SFAs induce inflammation through TLR4 in diet-induced obesity (DIO) models.
Both high-fat diets and high-fructose diets influence enterobacterial bacterial production and circulating levels of LPS/endotoxin by altering gut flora growth and composition and gut permeability [41–44]. Dietary lipids facilitate LPS incorporation into chylomicrons [45] and TLR4 is responsible for phagocytosis of gram-negative bacteria by gut enterocytes [46], each contributing to postprandial endotoxemia. Insulin resistant DIO and genetically obese mice and type 2 diabetic humans [41, 46–48] all exhibit elevated plasma LPS levels and endotoxemia is correlated with insulin resistance and atherogenic markers. Thus, chronic elevation of circulating gut-generated LPS or “metabolic endotoxemia” [49] would result in sustained, systemic pro-inflammatory stimulation of TLR4. Interestingly, germ-free mice or mice treated with antibiotics specific for gram-negative bacteria do not acquire high-fat diet-induced insulin resistance or other associated metabolic abnormalities [50–52]. Genetically obese ob/ob mice treated with an LPS inhibitor or in a CD14 KO background have reduced inflammation and metabolic abnormalities compared to normal ob/ob mice [51, 52] which suggests that these ob/ob phenotypes are partly mediated by gut LPS and TLR4 signaling.
Lipopolysaccharide(endotoxin) Directly Stimulates Cortisol Secretion by Human Adrenal Cells by a Cyclooxygenase-Dependent Mechanism
https://academic.oup.com/endo/article/146/3/1398/2500860
Interaction between stress hormones and phagocytic cells and its effect on the health status of dairy cows: A review
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566244/
High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage
https://doi.org/10.1016/j.bbrc.2019.11.158
Highlights:
• Feeding a high-fat diet (HFD) induced atrophy of the intestines.
• Feeding an HFD reduced the number of small intestinal T-cells, too.
• We defined these phenotypes as termed intestinal lipotoxicity.
• Intestinal lipotoxicity was caused by cytotoxicity from HFD-derived free fatty acids.
• Intestinal lipotoxicity exacerbated indomethacin-induced small intestinal damage.
In Japan and other Asian countries, increased fat uptake induced by a westernized diet is thought to be associated with an increased incidence of inflammatory bowel disease, colorectal cancer and food allergies; however, the mechanism for this remains unclear. High-fat diet (HFD)-fed mice are common animal models used to examine the effect of fat intake in vivo. HFDs are reported to exacerbate DSS-induced colitis and intestinal tumorigenesis, but the effect of HFDs on the intestines before disease induction is often overlooked. We found that the intestinal and gut-associated lymphoid tissue (GALT) morphology of HFD-fed mice differed from that of standard diet (SD)-fed mice. To clarify the mechanism by which fat intake increases intestinal diseases, we analyzed the morphological and immunological aspects of the intestines of HFD-fed mice as well as the molecular mechanisms and physiology.
Feeding an HFD for 3 weeks induced atrophy of the small intestine, colon and GALT and reduced the number of small intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). Feeding an HFD for only one day reduced the number of small intestinal (SI)-IELs and SI-LPLs. The effect of feeding a 3-week HFD continued for 2 weeks after returning to the SD. The effect of the HFD on the intestinal immune system was independent of the gut microbes. We hypothesized that the cytotoxicity of the abundant HFD-derived free fatty acids in the intestinal lumen impairs the intestinal immune system. Both saturated and unsaturated free fatty acids were toxic to intestinal T-cells in vitro. Orally administering free fatty acids reduced the number of SI-IELs and LPLs. Using a lipase inhibitor to reduce the luminal free fatty acids attenuated the HFD-induced changes in the intestinal immune system, while using a statin to reduce the serum free fatty acids did not.
Thus, HFD-induced free fatty acids damaged the intestines; this effect was termed “intestinal lipotoxicity”. Because sustained reduction of SI-LPLs after HFD feeding exacerbated indomethacin-induced small intestinal damage, lipotoxicity to the human intestines incurred by consuming a westernized diet in Japan may increase intestinal diseases such as IBD, colorectal cancer or food allergies.
Mouse and humans are different. Especially when it comes to eating fats. I think the worst type of diet is SAD which is excess calories diet high in everything carbs/sugars, the worst type of fats like trans fats, refined vegetable oils, high amount of fructose + inactivity + deficiency in key micronutrients and there you have great recipe for obesity, diabetes, heart disease.. I don't see a problem with high fat, low carb diet when it's from good foods and ideally when it cyclical so periods of high fat, low carb and periods of high carbs, lower fat.. I would also say for average fat people high fat, low carb is the easiest type of diet follow to lose weight... Because it's slows everything down, lowers appetite and stabilizes blood sugar. During my bodybuilding days I was doing low fat, carb cycling which is the hardest type of diet. It works really well to burn fat and keep metabolism high, but you are going crazy on diet like that. 🙂 Blood sugar and energy level up and down all the time, insane hunger..
I'am afraid all those keto/high fat diets are just playing around cortisol(stress hormone) levels and its influence over the immune system.
I've always wondered what makes keto diets so anti-inflammatory if they simultaneously elevate your cortisol. I suppose the idea that it suppresses the immune system serves as a pretty good explanation.
edit: on further thought, it's actually obvious given that cortisol directly acts as an immune system suppressor, but I didn't imagine its increase could result in such anti-inflammatory feedback;
Yeah, keto is highly anti inflammatory, ketones by themselves suppress NLRP3 inflammasome (https://pubmed.ncbi.nlm.nih.gov/25686106/).
But not all zero carb diets are keto - if one managed to eat enough proteins he/she will stay out of ketosis(could be always proved by ketone meter like "Freestyle").
Another potential problem is starting a day with caffeine to delay cortisol dump:
Caffeine Stimulation of Cortisol Secretion Across the Waking Hours in Relation to Caffeine Intake Levels
https://www.researchgate.net/publication/7561673_Caffeine_Stimulation_of_Cortisol_Secretion_Across_the_Waking_Hours_in_Relation_to_Caffeine_Intake_Levels
Stress-like adrenocorticotropin responses to caffeine in young healthy men
https://pubmed.ncbi.nlm.nih.gov/8951977/
The effects of oral caffeine (3.3 mg/kg, equivalent to 2-3 cups of coffee) on plasma adrenocorticotropin (ACTH) and cortisol (CORT) were tested in 47 healthy young men at rest in a double-blind, placebo-controlled, crossover study. Following caffeine, ACTH was significantly elevated at all times from 30 min to 180 min, and CORT was elevated from 60 min to 120 min (Fs > or = 8.4, ps < 0.01). Peak increases relative to placebo were: ACTH, 33% (+5.2 pg/ml) and CORT, 30% (+2.7 micrograms/dl) at 60 min postcaffeine
Mechanisms of Disease: the adrenocorticotropin receptor and disease
https://www.nature.com/articles/ncpendmet0165
The action of the peptide hormone adrenocorticotropin (ACTH) to stimulate glucocorticoid production by the adrenal gland
Linkage of CD8+ T cell exhaustion with high-fat diet-induced tumourigenesis
https://www.nature.com/articles/s41598-019-48678-0
Increased levels of hormones (such as oestrogen, insulin, insulin-like growth factor, and leptin), free fatty acid-induced production of reactive oxygen species, an altered intestinal microbiome and chronic inflammation are known to be associated with an increased cancer risk in obese subjects. However, the mechanism underlying the connection between obesity and cancer development remains elusive. Here, we show that a high-fat diet (HFD) promotes tumour initiation/progression and induces a phenotypic switch from PD-1− CD8+ non-exhausted T cells to PD-1+ CD8+ exhausted T cells in a murine breast cancer model. While PD-1− CD8+ non-exhausted T cells predominated in the mammary glands of normal diet (ND)-fed mice, PD-1+ CD8+ exhausted T cells accumulated in the developing tumours of HFD-fed mice. Gene expression profiles indicated that PD-1+ CD8+ T cells expressed higher levels of the tumour-trophic gene Opn and lower levels of the cytotoxic genes Ifng and Gzmb than did PD-1− CD8+ T cells. Our study provides a possible mechanistic linkage between obesity and cancer.
Anhedonia induced by high-fat diet in mice depends on gut microbiota and leptin
https://www.tandfonline.com/doi/full/10.1080/1028415X.2020.1751508
Objectives: Imbalanced nutrition and obesity are risk factors for depression, a relationship that in rodents can be modeled by depression-like behavior in response to high-fat diet (HFD). In this work, we examined the role of the intestinal microbiota and the adipocytokine leptin as potential mediators of the effects of HFD to induce anhedonia-like behavior and reduce self-care in mice.
Methods: Male mice were fed a control diet or HFD (60 kJ% from fat) for a period of 4 weeks, after which behavioral tests and molecular analyses (gut microbiome composition, intestinal metabolome, fecal fatty acids, plasma hormone levels) were performed. The role of the intestinal microbiota was addressed by selective depletion of gut bacteria with a combination of non-absorbable antibiotics, while the implication of leptin was examined by the use of leptin-deficient ob/ob mice.
Results: Antibiotic treatment reduced the HFD-induced weight gain and adiposity and prevented HFD-induced anhedonia-like behavior and self-care reduction. These effects were associated with a decrease in fecal fatty acids and intestinal microbiota-related metabolites including short-chain fatty acids, glucose and amino acids. Gut microbiota depletion suppressed the HFD-induced rise of plasma leptin, and the circulating leptin levels correlated with the anhedonia-like behavior and reduced self-care caused by HFD. The anhedonic effect of HFD was absent in leptin-deficient ob/ob mice although these animals gained more weight and adiposity in response to HFD than wild-type mice.
Discussion: The results indicate that anhedonia-like behavior induced by HFD in mice depends on the intestinal microbiome and involves leptin as a signaling hormone.
High-fat diet triggers obesity-related early infiltration of macrophages into adipose tissue and transient reduction of blood monocyte count
https://www.sciencedirect.com/science/article/pii/S0161589019304390
Infiltration of adipose tissue macrophages (ATMs) is a typical feature of obesity, and circulating immune cells may indicate immune cell accumulation. However, it remains unclear whether this is true in the early stages of obesity. This study aimed to define the role of blood monocytes in obesity and the relationship between blood monocytes and ATMs in early-stage obesity. Two groups of male C57BL/6 J mice were fed on a 60 % high-fat diet (HFD) or a 10 % fat normal diet (ND), respectively, and monitored at 1, 2, 3, 7, and 12 weeks. Populations of circulating blood monocytes (CD11b + CD115+), ATMs (F4/80+CD11b+), and their subtypes were collected and analyzed using flow cytometry and immunofluorescence. Some cytokines (TNF-a, IL-1β) and chemokines (CCL2, CCL7) were also analyzed by real-time PCR. HFD induced obesity, dramatic fat expansion, and accumulation of ATMs in mice after 12 weeks. However, an acute and transient reduction of circulating monocyte count, elevated expression of CD11c in ly6clow monocytes, and concurrent infiltration of ATMs into visceral adipose tissues (VAT) were observed as early as 1 week after initiating HFD. Further, HFD-induced changes in VAT, but not blood monocyte count, were partially reversed upon reverting to ND for 6 weeks. An acute but transient reduction of blood monocyte count was observed at the early stages of HFD feeding, which might be related to early infiltration of macrophages into adipose tissues.
Plasma leptin concentrations are highly correlated to emotional states throughout the day
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350520/
Previous work has shown that leptin appears to regulate the plasma levels of hormones such as adrenocorticotropic hormone (ACTH) and cortisol in humans and that it has antidepressant effects in animals. It is unknown whether fluctuations in circulating leptin levels are correlated to changes in human emotions. This study was conducted to determine whether minute-to-minute fluctuations in the plasma concentrations of human leptin were associated with psychological variables. Leptin was sampled every 7 min throughout the day in 10 healthy subjects (five men and five women) studied in a clinical research center, and visual analog scales were applied every hour. We found highly significant correlations between fluctuations in plasma leptin concentrations and three psychological variables: sadness, carbohydrate craving and social withdrawal.
We showed that during the course of the day increases in leptin levels are associated with decreased search for starchy foods, decreased feelings of sadness and increased social withdrawal. Our findings support the hypothesis that during the course of the day as leptin levels increase individuals subjectively feel happier (less sad) and have less inclination to interact socially. Conversely, when leptin levels decrease, we show increases in sadness and social cooperation, which might facilitate the search for food. We suggest that increased human leptin levels may promote positive feelings and that decreased leptin levels might modulate inner states that motivate and facilitate the search for nutrients.
https://newatlas.com/obesity-gut-brain-hormone-signal-leptin/61019/
Leptin is a hormone with a range of functions but it is probably best known for regulating appetite. Fat cells produce leptin, and the hormone communicates with the hypothalamus to let someone know when they should stop eating.
Obese people obviously have more fat cells, so they are known to have higher levels of leptin, however, this counter-intuitively does not result in a suppressed appetite. This scenario is called leptin resistance, and scientists weren't sure exactly what causes the body to block these leptin signals in the brain and cause a person to overeat.
"We didn't know how a high-fat diet or overeating leads to leptin resistance," says corresponding author Makato Fukuda, explaining the origins of the research. "My colleagues and I started looking for what causes leptin resistance in the brain when we eat fatty foods. Using cultured brain slices in Petri dishes we screened blood circulating factors for their ability to stop leptin actions. After several years of efforts, we discovered a connection between the gut hormone GIP and leptin."
GIP, or gastric inhibitory polypeptide, is secreted by the gut in response to food. It is part of a family of molecules called incretins, known to help regulate insulin and energy expenditure. Prior research has found GIP levels are raised in obese subjects, and they directly increase in relation to fat and sugar consumption. Animal studies have also revealed inhibiting GIP can protect against weight gain from a high-fat diet.
The new research for the first time found an association between GIP and leptin, as well as discovering GIP receptors on the hypothalamus, suggesting the molecule can enter the brain and plausibly affect appetite signaling. When GIP activity in the brain was blocked in obese animal models, the rodents ate less and lost weight, however, this same action did not occur in lean animals, suggesting GIP activity only plays a role in obesity or high-fat diet scenarios.
Homing in on the leptin connection, the researchers experimented with blocking GIP activity in mice engineered to be leptin deficient. In this instance, the obese animals did not respond at all to GIP inhibition, and continued overeating. This affirmed to the researchers that it seems to be GIP that modulates leptin resistance in obese subjects causing overeating and weight gain.
"… when eating a balanced diet, GIP levels do not increase and leptin works as expected, triggering in the brain the feeling of being full when the animal has eaten enough and the mice stop eating," says Fukuda. "But, when the animals eat a high-fat diet and become obese, the levels of blood GIP increase. GIP flows into the hypothalamus where it inhibits leptin's action. Consequently, the animals do not feel full, overeat and gain weight. Blocking the interaction of GIP with the hypothalamus of obese mice restores leptin's ability to inhibit appetite and reduces body weight."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275238/
Quote from rockarolla on May 31, 2021, 4:50 amBut not all zero carb diets are keto - if one managed to eat enough proteins he/she will stay out of ketosis(could be always proved by ketone meter like "Freestyle").
Oops, proteins overeating might be not the best idea:
Meal stimulation of cortisol secretion: A protein induced effect
https://www.sciencedirect.com/science/article/abs/pii/002604958190055X
Cortisol and ACTH secretion was studied in 52 healthy subjects who were fasted or fed various diets: standard, high fat, high carbohydrate, high protein. Subjects fed the high protein diet (4gm/kg body weight) showed significant increases in cortisol both at 30 and 60 min after the 1200 hr meal and 30 min after the 1600 hr meal. Increases in cortisol, of a smaller magnitude, were also seen after both the 1200 and 1600 hr meals in each of the diets with 1 gm protein/kg body weight (standard, high fat, high carbohydrate). ACTH was significantly increased following the 1200 hr and 1600 hr meals with the high protein diet. We conclude that dietary protein plays an important role in meal stimulated cortisol release.
Explains the uprise of low carb/keto diets?
A High-Fat Diet Induces Lower Systemic Inflammation than a High-Carbohydrate Diet in Mice
https://www.liebertpub.com/doi/10.1089/met.2020.0116
Background: We previously established that male Swiss mice (Mus musculus) receiving a high-fat diet (HFD) during 8 weeks exhibit similar caloric ingestion and body weight (grams) compared with mice fed a high-carbohydrate diet (HCD). HFD mice exhibit a lower inflammatory state than an HCD in the liver, skeletal muscle, and brain. In addition, we demonstrated that HFD and HCD modulated fatty acids (FA) composition in these tissues. In this study, our objective was to compare HFD mice and HCD mice in terms of systemic inflammation.
Methods: Saturated FA (SFA), monounsaturated FA, omega-6 polyunsaturated FA (n-6 PUFA), and n-3 PUFA were evaluated at the time points 0, 1, 7, 14, 28, and 56 days after starting the administration of the diets. We investigated n-6 PUFA:n-3 PUFA, SFA:n-3 PUFA, palmitic acid:α-linolenic acid (ALA), and myristic acid:docosahexaenoic acid (DHA) ratios as potential serum biomarkers of systemic inflammation. We also measured the serum levels of basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible protein 10 (IP-10), interferon gamma (IFN-γ), interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, macrophage inflammatory protein-1α (MIP-1-α), monocyte chemotactic protein 1 (MCP-1), monokine induced by IFN-γ (MIG), and tumor necrosis factor α (TNF-α).
Results: The HFD group had lower (P < 0.05) n-6 PUFA:n-3 PUFA, palmitic acid:ALA, myristic acid:DHA ratios, and lower plasma levels of proinflammatory cytokines (IFN-γ, MIG, GM-CSF, and IL-6).
Conclusion: The HFD mice showed lower systemic inflammation compared with a caloric ingestion–body weight-matched control HCD mice.