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High-fat, high-sugar diet induces splenomegaly that is ameliorated with exercise and genistein treatment



Objective We tested the effect of exercise training and genistein treatment on splenomegaly in mice fed a high-fat, high-sugar diet (HFSD). Results Male and female C57BL6 mice fed HFSD containing 60% fat along with drinking water containing 42 g/L sugar (55% sucrose/45% fructose) for 12 weeks exhibited significant obesity, hyperglycemia, and elevated plasma IL-6 levels. This was accompanied by splenomegaly characterized by spleen weights 50% larger than mice fed standard chow (P < 0.05) with enlarged rad and white pulps. Mice fed HFSD and treated with a combination of exercise (30 min/day, 5 days/week) and genistein (600 mg genistein/kg diet) had reduced spleen weight (P < 0.05). The decrease in spleen weight was associated with a significant improvement in red-to-white pulp area ratio and plasma glucose and IL-6 (P < 0.05). Our findings indicate that reversal of splenomegaly by regular exercise and genistein treatment may be important in the clinical management of HFSD-induced obesity.
Buchanetal. BMC Res Notes (2018) 11:752
High-fat, high-sugar diet induces
splenomegaly thatisameliorated withexercise
andgenistein treatment
Levi Buchan1, Chaheyla R. St. Aubin2, Amy L. Fisher2, Austin Hellings1, Monica Castro3, Layla Al‑Nakkash4,
Tom L. Broderick5 and Jeffrey H. Plochocki3,6*
Objective: We tested the effect of exercise training and genistein treatment on splenomegaly in mice fed a high‑fat,
high‑sugar diet (HFSD).
Results: Male and female C57BL6 mice fed HFSD containing 60% fat along with drinking water containing 42 g/L
sugar (55% sucrose/45% fructose) for 12 weeks exhibited significant obesity, hyperglycemia, and elevated plasma IL‑6
levels. This was accompanied by splenomegaly characterized by spleen weights 50% larger than mice fed stand‑
ard chow (P < 0.05) with enlarged rad and white pulps. Mice fed HFSD and treated with a combination of exercise
(30 min/day, 5 days/week) and genistein (600 mg genistein/kg diet) had reduced spleen weight (P < 0.05). The
decrease in spleen weight was associated with a significant improvement in red‑to‑white pulp area ratio and plasma
glucose and IL‑6 (P < 0.05). Our findings indicate that reversal of splenomegaly by regular exercise and genistein treat‑
ment may be important in the clinical management of HFSD‑induced obesity.
Keywords: High‑fat diet, High‑sugar diet, Spleen, Exercise, Genistein
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Obesity, type 2 diabetes mellitus, and other metabolic
disorders are being reconceptualized as inflammatory
conditions [1, 2]. For example, obesity induced by high-
fat, high-sugar diet (HFSD) is associated with prolonged
elevation of proinflammatory serum markers such as
IL-6 and inflammation in peripheral tissues, as well as
metabolic dysregulation, including insulin and leptin
resistance [3, 4]. Although the effects of diet-induced
metabolic dysregulation and inflammation are widely
documented in many organs, its effects on spleen mor-
phology have yet to be thoroughly characterized.
e spleen is the largest secondary lymphoid organ
in the body and is composed of two functional regions,
white and red pulp. White pulp is lymphoid tissue
containing immune cells that target blood-borne patho-
gens, whereas red pulp is a site of erythrophagocytosis
[5, 6]. Inflammation induced by HFSD has been shown
to modulate splenic function by causing increased phos-
phatidylserine externalization of red blood cells and
thus promoting the interaction with erythrophagocy-
tosis macrophages [6], and by inducing extramedul-
lary hematopoiesis of monocyte-like cells secondary to
inflammation [7]. ese changes in splenic function and
morphology have been implicated in the pathogenesis of
diabetes and obesity-related cardiovascular disease and
kidney disease [6, 8]. erefore, therapeutic modalities
that maintain normal splenic morphology in the obese
condition may prove beneficial to long-term health.
In this study, we examine metabolic and proinflamma-
tory markers, spleen weight, and spleen histomorphome-
try in mice fed a HFSD and treated with either exercise or
the isoflavone genistein, or both. Treatment with exercise
and isoflavones have been shown to ameliorate periph-
eral inflammation through antioxidative actions and by
Open Access
BMC Research Notes
6 Department of Medical Education, College of Medicine, University
of Central Florida, 6850 Lake Nona Blvd, Orlando, FL 85308, USA
Full list of author information is available at the end of the article
Page 2 of 6
Buchanetal. BMC Res Notes (2018) 11:752
reducing levels of proinflammatory cytokines [3, 9, 10].
In this study, we hypothesize that exercise and genistein
treatment in mice fed a HFSD mitigates diet-induced
changes in spleen weight and morphology.
Main text
Fifty female and 50 male mice of the strain C57BL6 (Jax
Labs, ME, USA) were used in the study. At the age of
6weeks, the mice were randomly divided into 5 treat-
ment groups of 10 mice per sex. Treatment groups were
assigned as follows: (1) untreated control mice, (2) mice
fed a HFSD, (3) mice fed a HFSD and treated with exer-
cise, (4) mice fed a HFSD and treated with genistein, (5)
and mice fed a HFSD and treated with exercise and gen-
istein. Treatment was administered for 12weeks. Mice in
the HFSD groups were fed pellets with 60% fat, 20% pro-
tein and 20% carbohydrate (Dyets Inc. Bethlehem, PA,
USA) and given 42g/L sugar dissolved in drinking water
(55% fructose/45% sucrose). is diet induces significant
visceral obesity and insulin resistance in the C57BL/6
mouse [11]. Control mice were given standard drinking
water and rodent chow that contained 20.3 g protein,
66g carbohydrate, and 5g fat. All foods and liquids were
administered adlibitum. Exercise treatment consisted of
low-intensity treadmill running for 30min/day, 5days/
week. Exercise of this duration and intensity was chosen
because it has been shown to reduce insulin resistance
in C57BL/6 mice with diet-induced obesity [12]. Gen-
istein treatment was administered at 600mg genistein/
kg HFSD diet (Dyets Inc., PA, USA). We have previously
found this genistein dose incorporated into diet is suf-
ficient to produce significant increases in free genistein
in plasma and to benefit bone and gut health [13, 14].
During the study, mice were housed at a temperature of
22°C with a light/dark period of 12-h. Use of the ani-
mals was approved by the Institutional Animal Care and
Use Committee at Midwestern University. e protocol
of the experiment complied with the National Institutes
of Health’s Guide for the Care and Use of Laboratory
Following sacrifice at an age of 4months, spleens were
harvested, weighed, and embedded in paraffin blocks.
Spleens were then sectioned longitudinally in the mid-
line at 5 μm thickness and stained with hematoxylin
and eosin (H&E) for histological evaluation under light
microscopy. ImageJ (v1.6, NIH) was used to measure
the area of the spleen and the ratio of white to red pulp,
calculated as [(red pulp area white pulp area)/white
pulp area]. Enlargement of one or both of these splenic
regions may indicate dysfunction. Plasma was collected
for measurement of glucose (Autokit, Wako Diagnostics,
Richmond, VA, USA), insulin, and IL-6 (Milliplex Assay,
Millipore, Billerica, MA, USA) following the manufac-
turers’ instructions. Two-way ANOVA was used to test
for differences among the treatment groups and between
females and males. Significance was set at P < 0.05. Sta-
tistical analyses were conducted using SPSS Statistics 25
software (IBM, USA).
Food intake measured by weight was similar in mice fed
HFSD and lean mice fed a standard diet (P > 0.05), yet
mice fed HFSD had significantly greater body mass than
lean mice (P < 0.05, Fig. 1). Mice fed HFSD and treated
with genistein had reduced food intake and body mass in
comparison to mice fed HFSD alone (P < 0.05). Analysis
of plasma markers showed mice treated with HFSD had
elevated glucose, insulin, and IL-6 in comparison to lean
mice fed standard diet (P < 0.05, Fig. 1). Treatment with
exercise and genistein in combination reduced plasma
glucose and IL-6 in mice fed HFSD (P < 0.06). When com-
paring males and females within each treatment group,
we found males fed a standard diet had greater body
masses, food intake, and plasma glucose and insulin
levels than females given the same diet (P < 0.05). Male
mice also had higher body mass and insulin levels than
females in every treatment group except HFSD + gen-
istein (P < 0.05).
Comparisons of spleen weights showed mice fed HFSD
had significantly enlarged spleens relative to lean mice
(P < 0.05, Fig.2). However, there was no difference in red-
to-white pulp ratio between these treatment groups, indi-
cating the increase in splenic weight in HFSD mice is due
to expansion of both the red and white pulps (P > 0.05,
Fig.2). Mice fed HFSD and treated with both genistein
and exercise had reduced spleen weight and red-to-
white pulp ratios in comparison to mice fed HFSD alone
(P < 0.05). Male and female mice fed HFSD responded
similarly to treatment with exercise and genistein alone
and in combination (Fig.2). Microscopic examination of
the spleens found increased cellularity in the red pulps
of mice fed a HFSD in comparison to mice fed a stand-
ard diet and HFSD mice treated with exercise and/or
genistein (Fig.3). e red pulps of mice fed HFSD con-
tained numerous macrophages, which were not present
to the same extent in mice of the other treatment groups
Our results show that HFSD significantly alters splenic
morphology. Mice fed a HFSD exhibited significant
splenic enlargement in comparison to control mice
after 12 weeks of treatment. Given that 6 weeks of
high-fat diet administration in rats does not signifi-
cantly increase spleen weight [15], our findings suggest
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Buchanetal. BMC Res Notes (2018) 11:752
doubling the treatment period or the addition of sugar
to the diet may be needed to induce splenomegaly.
We found no significant difference in the ratio of red-
to-white pulp area in mice fed a HFSD. is suggests
splenomegaly is likely attributed to concomitant mor-
phological changes in both the red and white pulp.
Altukkaynak etal. [16] found treatment with high fat
diet causes sinusoids and surrounding tissue to expand
in both the red and white pulps, rather than finding
histological changes specific to one pulp. is is con-
sistent with our microscopic observations of the spleen.
We further observed numerous macrophages adjacent
to the sinusoids of mice fed a HFSD. While HFSD has
yet to be studied in the spleen, administration of a
high fat diet to mice has been shown to enhance eryth-
rophagocytosis by macrophages [6]. Our observation of
increased macrophage presence in the spleen indicates
this also occurs with HFSD.
Fig. 1 Body mass (a), food intake (b), and plasma levels of glucose (c), insulin (d), and IL‑6 (e) by treatment group. *Significant difference between
lean mice fed standard diet and mice fed HFSD (P < 0.05); significant difference with mice fed HFSD (P < 0.05); significant difference between males
and females given the same treatment (P < 0.05). LN, lean mice fed standard diet (n = 10 females, 8 males); HFSD, high‑fat, high‑sugar diet (n = 9
females, 9 males); Ex, exercise (n = 9 females, 10 males); Gen, genistein (n = 8 females, 8 males); GenEx, genistein and exercise (n = 10 females, 8
males). Data are expressed as mean ± 2 SE
Fig. 2 Analysis of spleen weight (a) and ratio of red pulp area to white pulp area of the spleen (b) by sex and treatment group. As the ratio
approaches 0.0, there is greater white pulp area relative to red pulp area. *Significant difference between lean mice fed standard diet and mice
fed HFSD (P < 0.05); significant difference with mice fed HFSD (P < 0.05). LN, lean mice fed standard diet (n = 10 females, 8 males); HFSD, high‑fat,
high‑sugar diet (n = 9 females, 9 males); Ex, exercise (n = 9 females, 10 males); Gen, genistein (n = 8 females, 8 males); GenEx, genistein and exercise
(n = 10 females, 8 males). Data are expressed as mean ± 2 SE
Page 4 of 6
Buchanetal. BMC Res Notes (2018) 11:752
A central goal of our study was to determine the thera-
peutic value of exercise and the isoflavone genistein on
reducing splenomegaly. We show treatment with exer-
cise and genistein in combination inhibits the formation
of splenomegaly in mice fed a HFSD. Genistein inhibits
angiogenesis by inhibiting proliferation of endothelial
cells [17]. It is possible that the anti-angiogenic effects
of genistein prevent sinusoidal dilation in the spleen,
thereby ameliorating splenomegaly associated with
HFSD. is has been hypothesized as an explanation for
how genistein treatment reduces splenomegaly in mice
with malaria-infected red blood cells, and may be acting
in a similar manner here [18]. Genistein also blocks the
ingestion of RBCs by macrophages through its actions as
a tyrosine kinase inhibitor [19]. Erythrophagocytosis is
a major cause of splenomegaly and interruption of this
process in the red pulp by genistein may help explain its
influence on spleen weight in our study. It may also help
explain why the red-to-white pulp ratio is decreased in
mice fed HFSD and treated with genistein and exercise.
However, additional research is required to explicate the
precise mechanism of the contribution of genistein to
splenomegaly prevention.
Splenic volume has been reported to decrease in vol-
ume during exercise, likely from contractile reticular cells
within the splenic stroma [20, 21]. However, this change
appears to be transient, although long-term data are lack-
ing [22]. It is perhaps more likely that the contribution
of exercise to the observed decrease in spleen weight is
associated with reductions in obesity-related inflamma-
tion. Exercise is protective against central obesity and
insulin resistance, and is associated with a reduction in
proinflammatory serum markers [23]. Exercise modu-
lates the function of immune cells that are abundant in
the spleen, namely lymphocytes and macrophages [24,
25]. Even light exercise is sufficient to reduce circulat-
ing proinflammatory cytokines like TNF secreted by
lymphocytes and macrophages [26, 27]. Alterations in
immune cell function, particularly in the obese condition
[28], may contribute to reductions in spleen volume.
Fig. 3 Representative histological sections of the spleen for each treatment group. Note the high cellularity of the control HFSD‑fed mice, which
is not present to the same extent in the HFSD treated with exercise and/or genistein. Mice fed HFSD also have numerous macrophages in the red
pulp (asterisks) in comparison to the other treatment groups. Splenic morphological appearance did not differ by sex. LN, lean mice fed standard
diet (n = 10 females, 8 males); HFSD, high‑fat, high‑sugar diet (n = 9 females, 9 males); Ex, exercise (n = 9 females, 10 males); Gen, genistein (n = 8
females, 8 males); GenEx, genistein and exercise (n = 10 females, 8 males). RP, red pulp; WP, white pulp. Histological analysis was conducted on all
100 mice. H&E stain. Scale bar 50 μm
Page 5 of 6
Buchanetal. BMC Res Notes (2018) 11:752
e efficacy of treatment with a combination of gen-
istein and exercise in the HFSD-fed mice on spleno-
megaly is further corroborated by reductions in body
mass and plasma glucose and IL-6 levels also identified
in this treatment group. ese results suggest genistein
and exercise in combination improve metabolic func-
tion and inhibit inflammation systemically. Treatment
with genistein and exercise in combination may mitigate
splenomegaly by beneficially affecting glucose and IL-6
pathways. Glucose intake induces oxidative stress at the
cellular and molecular levels that causes inflammation
through secretion of IL-6 [29], a proinflammatory marker
associated with the obese condition and complications
such as cardiovascular disease [30, 31]. Cells incubated
with genistein exhibit decreased IL-6 production [32,
33]. IL-6 production is also modulated by glucose cellu-
lar uptake during exercise [34, 35]. e combined effects
of genistein and exercise on glucose uptake and IL-6
expression may be responsible for the reduction in spleen
weight noted in the current study, and may likely have
benefits beyond the spleen. However, additional data are
needed to elucidate the precise effects of genistein and
exercise treatment in the HFSD-induced obese condition.
In summary, this study presents novel findings that
augment the current understanding of how splenic mor-
phology is influenced by diet. We show that, (1) HFSD
administered over a 12-week period is sufficient to cause
splenomegaly in mice, (2) combined exercise and gen-
istein treatment may reverse splenic enlargement associ-
ated with HFSD, and (3) the reduction in splenomegaly
with combined exercise and genistein treatment directly
correlates with reductions in plasma glucose and IL-6
levels. ese findings may have implications for the treat-
ment of inflammation and splenomegaly associated with
HFSD diet.
Our study is limited in several ways. To better define
changes to splenic pulp cellular composition, immuno-
histochemistry should be conducted to identify prolifera-
tion in immune cell populations. Red blood cell labeling
in conjunction with a splenic phagocytosis assay would
also better inform our understanding of alterations in
erythrophagocytosis for each treatment. Interpretations
of our findings should be qualified by these limitations.
HFSD: high‑fat, high sugar diet; Ex: exercise; Gn: genistein; RP: red pulp; WP:
white pulp.
Authors’ contributions
LA, TLB, and JHP contributed to planning the experiments. AF, CS exercise
trained the mice for the 12 week study. AF, CS, LB, AH, MC, LA, and JHP
conducted the experimental analyses. LB and JHP drafted the manuscript.
All other authors edited and revised the manuscript. LA, TLB, and JHP were
responsible for securing the funding. All authors read and approved the final
Author details
1 Arizona College of Osteopathic Medicine, Midwestern University, Glendale,
AZ, USA. 2 College of Graduate Studies, Midwestern University, Glendale, AZ,
USA. 3 Department of Anatomy, College of Graduate Studies and Arizona
College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA.
4 Department of Physiology, College of Graduate Studies and Arizona College
of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA. 5 Depart‑
ment of Physiology, Laboratory of Diabetes and Exercise Metabolism, College
of Graduate Studies and Arizona College of Osteopathic Medicine, Midwest‑
ern University, Glendale, AZ, USA. 6 Department of Medical Education, College
of Medicine, University of Central Florida, 6850 Lake Nona Blvd, Orlando, FL
85308, USA.
We wish to acknowledge the Arizona Alzheimer’s Consortium (LA, TLB, JHP)
and Midwestern University Intramural Funds (LA, TLB, and JHP) for funding our
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The datasets used in the current study are available from the corresponding
author by request.
Consent for publication
Not applicable.
Ethics approval
The protocol for this study was approved by the Midwestern University Institu‑
tion Animal Care and Use Committee (IACUC Protocol #2880).
Midwestern University and Arizona Alzheimer’s Consortium funded the study.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Received: 6 August 2018 Accepted: 17 October 2018
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... The metabolic data from mice fed an HFHS diet were previously published [25]. Briefly, mice fed an HFHS diet for 12 weeks had significantly greater body mass, higher plasma glucose, insulin, and IL-6 levels than control mice fed a standard diet (p < 0:05). ...
... These are well-documented hallmarks of AD and are consistent with previous studies [26,45]. The HFHS diet used in this study was sufficient to induce visceral obesity, hyperglycemia, and insulin resistance in the C57BL/6 mice [25]. Increasing evidence suggests that insulin resistance is associated with AD pathology. ...
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In recent decades, a shift in the nutritional landscape to the Western-style diet has led to an unprecedented rise in the prevalence of obesity and neurodegenerative diseases. Consumption of a healthy diet and engaging in regular physical activity represents safe and affordable approaches known to mitigate the adverse consequences of the Western diet. We examined whether genistein treatment, exercise training, and a combination treatment (genistein and exercise training) mitigated the effects of a Western diet-induced by high-fat, high-sugar (HFHS) in brain of female mice. HFHS increased the amyloid-beta (Aβ) load and phosphorylation of tau, apoptosis, and decreased brain-derived neurotrophic factor (BDNF) levels. Exercise training and genistein each afforded modest protection on Aβ accumulation and apoptosis, and both increased BDNF. The greatest neuroprotective effect occurred with combination treatment. BDNF and all markers of Aβ accumulation, phosphorylation of tau, and apoptosis were improved with combined treatment. In a separate series of experiments, PC12 cells were exposed to high glucose (HG) and palmitate (PA) to determine cell viability with genistein as well as in the presence of tamoxifen, an estrogen receptor antagonist, to assess a mechanism of action of genistein on cell apoptosis. Genistein prevented the neurotoxic effects of HG and PA in PC12 cells and tamoxifen blocked the beneficial effects of genistein on apoptosis. Our results indicate the beneficial effects of genistein and exercise training on HFHS-induced brain damage. The benefits of genistein may occur via estrogen receptor-mediated pathways.
... In this regard, research on organs enriched with macrophages-the liver and spleen-is especially interesting in Type 2 diabetes [24,25]. In general, effects of trehalose in the heart have been poorly studied, although there are some data on a positive influence of trehalose in cardiometabolic diseases [26] . It was shown that trehalose upregulates cardiac autophagy marker LC3-II at 4 weeks after myocardial infarction, indicating that trehalose induces autophagy in the heart in vivo [27]. ...
... Spleen weight was ~2-fold greater in untreated db/db mice than in untreated C57BL/6 mice (p < 0.001, Figure 4). This finding is possibly attributable to enhanced functioning of the spleen or even splenomegaly in Type 2 diabetes as a consequence of liver steatosis (Buchan et al., 2018). In comparison with C57BL/6 mice, blood glucose concentration was significantly (p < 0.001) higher in db/db mice ( Figure 5A), as was glycated hemoglobin, % (p < 0.001), ( Figure 5B), whereas trehalose treatment significantly (p < 0.01) reduced both parameters ( Figure 5A,B). ...
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Db/db mice (carrying a mutation in the gene encoding leptin receptor) show autophagy suppression. Our aim was to evaluate the effect of autophagy inducer trehalose on liver and heart autophagy in db/db mice and to study inflammation dysregulation and the suitability of chitinases' expression levels as diabetes markers. Thirty-eight male db/db mice and C57/BL mice (control) were used. The db/db model manifested inflammation symptoms: overexpression of TNF-α in the spleen and underexpression of IL-10 in the liver and spleen (cytokine imbalance). Simultaneously, we revealed decreased expression of chitotriosidase (CHIT1) and acid mammalian chitinase (CHIA) in the liver of db/db mice. CHIA expression in db/db mice is significantly lower only in the spleen. Tre-halose treatment significantly reduced blood glucose concentration and glycated hemoglobin. Treatment of db/db mice by trehalose was followed by increased autophagy induction in the heart and liver (increased autolysosomes volume density studied by morphometric electron-microscopic method). Trehalose exerted beneficial cardiac effects possibly via increased lipophagy (uptake of lipid droplets). The autophagy activation by trehalose had several positive effects on the heart and liver of db/db mice; therefore, lipophagy activation seems to be a promising therapy for diabetes.
... An intraperitoneal glucose tolerance test (GTT) was performed in mice at week 3 and 9. Mice were fasted for 4 h prior to an intraperitoneal administration of 1.5 mg/g body weight glucose solution (Sigma-Aldrich, St. Louis, MO, USA). Baseline measurement of glucose concentration was completed prior to intraperitoneal administration of glucose (0 min) and at 15,30,60,90, and 120 min after administration of glucose. Blood samples were collected by a needle prick of the tail vein at each time point to determine glucose concentration (mmol/L) using a glucometer (Accu-Chek ® , Roche Diabetes Care, Pretoria, South Africa). ...
... Although these observations are common features of splenomegaly or spleen enlargement [29], a primary feature is an increase in splenic weight which was not observed in the current study. Splenic enlargement is found to persist in the chronic stages of obesity (long-term feeding) [30]. Based on the observations in the current study, it is suggested that the initial effects of DIO on the spleen may include necrosis, sinusoid dilatation and fibrosis, which may later result in splenic enlargement. ...
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Despite obesity being a major health concern, information on the early clinical changes that occur in plasma and tissues during obesity development and the influence of sexual dimorphism is lacking. This study investigated changes in tissue and organ histology, macrophage infiltration, plasma hormones, lipid, and chemokine and cytokine levels in mice fed on a high fat diet for 11-weeks. An increase in adiposity, accompanied by adipocyte hypertrophy and macrophage infiltration, was observed to be significantly greater in males than females. Important changes in cell morphology and histology were noted in the lungs, liver, kidney, spleen, and heart, which may indicate early signs for developing obesity associated comorbidities. Leptin, but not adiponectin, was significantly altered during weight gain. Additionally, leptin, but not adiposity, correlated with insulin levels. Interestingly, GM-CSF, TNFα, and IL-12 (p70) were not produced in the early stages of obesity development. Meanwhile, the production of MCP-1, IP-10, RANTES, IL-10, IL-6, KC, and IL-9 were greatly influenced by sexual dimorphism. Importantly, IL-6/IL-10 axis of anti-inflammatory cytokine regulation was observed only in females and may account for their significantly lower weight gain compared to males. This study provides new knowledge on how sexual dimorphism may influence the development of obesity and associated comorbidities.
... Our results agree with studies that confirmed the significant alterations in the splenic tissue weight of diabetic rat groups [27]. Both current diabetic (G1) and diabetic rats immunized with the influenza vaccine (G2) group showed expansion of the red and white pulp, indicating that there is an enlarged spleen compared to the control rat group at day 21 [28]. ...
... Those authors concluded that red blood cell dysfunction occurs early (within weeks) during diet-induced obesity. In a later study comparing mice on a hypercaloric diet with controls, spleen size was found to be increased and more macrophages were observed in the spleen of mice on the hypercaloric diet (Buchan et al., 2018). We therefore suggest that the gain in body fat in the present study increased red blood cell phagocytosis, which contributed to the lower Hct. ...
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This study examined the effect of altered body weight (BW) and body fat content on exercise performance and recovery. Nine horses were divided into two groups, and changes in BW and fat content were induced by feeding a high (HA) or restricted (RA) energy allowance for 36 days in a cross-over design. In the last week of each treatment, BW and body condition score (BCS) were recorded, body fat percentage was estimated using ultrasound, and a standardized incremental treadmill exercise test (SET) and competition-like field test were performed (scored by judges blinded to treatments). Blood samples were collected, and heart rate (HR), rectal temperature (RT), and respiratory rate (RR) were also recorded. Objective locomotion analyses were performed before and after the field test. Body weight, body fat percentage, and BCS were higher (5-8%) in HA than in RA horses (p < 0.05). In SET, HA horses showed higher HR, plasma lactate concentration, RR, and RT than RA horses (p < 0.05), and lower VLa4 , hematocrit (Hct), plasma glucose, and plasma NEFA concentrations (p < 0.05). Hct was also lower in HA horses in the field test, while RA horses showed higher scores (p < 0.05). After both tests, resting plasma lactate concentrations were reached faster in RA than in HA horses (p < 0.05). Objective locomotion asymmetry was higher in HA than in RA (p < 0.05). These results clearly show that increased BW and body fat content in horses lower physiological fitness in terms of VLa4 , plasma lactate removal, Hct levels, plasma glucose availability and reduce true performance evaluated by blinded judges.
... Dosages of these strains were established at 1 × 10 9 CFU/mouse based on in vitro studies. To induce significant obesity and IR in the mice, all HFD groups were fed a diet containing 60% fat, 20% protein, and 20% carbohydrates, and additionally, the mice were provided drinking water containing 42 g/L sugar (55% fructose/45% sucrose) [28]. The ND group was supplied a diet containing 14% fat, 21% protein, and 64% carbohydrates. ...
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The purpose of this study was to evaluate the capacity of Lactiplantibacillus plantarum MG4296 (MG4296) and Lacticaseibacillus paracasei MG5012 (MG5012) on insulin resistance (IR) and diabetes-related metabolic changes in palmitic acid (PA)-induced HepG2 cells and high-fat diet-induced mice. In vitro, cell-free extracts of MG4296 and MG5012 alleviated IR by increasing glucose uptake and glycogen content in PA-induced insulin-resistant HepG2 cells. In vivo, MG4296 and MG5012 supplementation markedly decreased body weight and glucose tolerance. Administration of both strains also improved serum glucose, glycated hemoglobin, insulin, triglyceride, LDL/HDL ratio, and homeostatic model assessment of IR (HOMA-IR). Histopathological analysis of liver tissue demonstrated a significant reduction in lipid accumulation and glycogen content. Moreover, MG4296 and MG5012 treatment enhanced phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) expression in the liver. Overall, MG4296 and MG5012 could prevent HFD-induced glucose tolerance and hyperglycemia by improving IR. Therefore, L. plantarum MG4296 and L. paracasei MG5012 could be useful as new probiotics candidates to improve T2DM.
... This increase in the relative weight in EG1 can be explained in part by the increase in red pulp, as well as the increase in CD4 + cells in this area at the end of the first week of training, corroborating with these data there was an increase in proportion of monocytes and lymphocytes marked in the spleen up to 120h after exercise 26 . The state of increased systemic inflammation may contribute to the increase in splenic weight, since there was an occurrence of splenomegaly with increased cellularity and expansion in the red pulp in obese rats 38 . Intense long exercise can lead to higher levels of inflammatory mediators 41,42 , it is not yet known but the increased inflammation caused by the impact of the training demand in the present study may have contributed to the organ increase at the end of the first week of training, however more research is needed on the subject. ...
Aims: Excessively intense physical training can compromise the functionality of the immune system and contribute to the appearance of symptoms associated with overtraining syndrome (OTS). The aim of this study was to analyze the splenic morphological changes in Wistar rats submitted to demanding training. Methods: The animals were randomly assigned to 2 groups; control group (CG) and exercise group (EG), animals in the EG group were sacrificed after 1 (EG1) and 3 weeks (EG3) of training. The animals were stimulated to run on the treadmill (-20º; from 25m/min, with a progressive increase of 1.25m/minute at each session; 1 hour/day) 6 days/ week. Body weight, food intake, appearance of hair, behavior and ability of animals to perform the imposed work were assessed during the protocol. The spleen was collected for histological analysis and immunohistochemical identification of CD4+ T lymphocytes and CD8+ T cells and NF-kB transcription factor. Results: The protocol did not induce OTS, however, decreases were observed in areas of white pulp in EG3 in relation to the other groups. The training induced a decrease in splenic CD4+ T cells with an increase in CD8+T cells. The training increased the expression of NF-κB P65 compared to sedentary animals. Conclusions: In conclusion, even without manifestation of OTS, strenuous physical training, alter the histological and immunological structures of the spleen, suggesting in part a compromise in the functionality of the immune system.
... In line with previous studies (Kakimoto and Kowaltowski, 2016), the liver weight more than doubled (111% increase) between 20% and 55% fat in CAS-fed animals and only increased by 23% in the corresponding WPI-fed animals ( Figure 3D), suggesting ectopic fat accumulation in the livers of CAS-but not WPI-fed mouse groups. High-fat feeding could also induce splenomegaly, leading to accumulation of macrophages and other cellular/histological changes in the spleen (Altunkaynak et al., 2007;Buchan et al., 2018). Importantly, intake of 40% and 55% fat induced splenomegaly in those eating CAS, whereas the increase of dietary fat in the corresponding WPI diets did not change the weight of the spleen ( Figure 3D). ...
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We investigated how protein quantity (10%–30%) and quality (casein and whey) interact with dietary fat (20%–55%) to affect metabolic health in adult mice. Although dietary fat was the main driver of body weight gain and individual tissue weight, high (30%) casein intake accentuated and high whey intake reduced the negative metabolic aspects of high fat. Jejunum and liver transcriptomics revealed increased intestinal permeability, low-grade inflammation, altered lipid metabolism, and liver dysfunction in casein-fed but not whey-fed animals. These differential effects were accompanied by altered gut size and microbial functions related to amino acid degradation and lipid metabolism. Fecal microbiota transfer confirmed that the casein microbiota increases and the whey microbiota impedes weight gain. These data show that the effects of dietary fat on weight gain and tissue partitioning are further influenced by the quantity and quality of the associated protein, primarily via effects on the microbiota.
Deregulated glucose homeostasis leads to a life-threatening metabolic disorder known as diabetes. The insulin deficiency and hyperglycaemic condition related to diabetes cause dysregulation of the immune system. The aim of the present study was to evaluate the combined efficacy of melatonin and insulin was evaluated in attenuation of lipopolysaccharide (LPS) caused inflammation, macrophage functional impairment, and oxidative stress in the spleen of diabetic mice.Streptozotocin was given for induction of diabetes. Diabetes mice were divided into two sets. Set-1 contained control, diabetes, diabetes insulin treated, diabetes melatonin treated, and diabetes melatonin and insulin treated groups of mice. In set II, the same number of groups as those of set I were challenged with a single dose of LPS. LPS caused a significant increase in oxidative stress, circulatory proinflammatory cytokines, significant suppression of antioxidant defense system, and phagocytic index in diabetic mice. Melatonin and insulin significantly improved the adverse effects caused by LPS treatment in diabetic mice. The present study noted that combined treatment of melatonin and insulin was more effective in attenuating LPS-induced devastating effects in laboratory mice. Therefore, the present study may suggest a combinatorial approach in the therapeutic use of melatonin and insulin to improve such devastating conditions.
Objectives: This study aimed to evaluate the effect of vagotomy, when associated with splenectomy, on adiposity and glucose homeostasis in Wistar rats. Methods: Rats were divided into 4 groups: vagotomized (VAG), splenectomized (SPL), VAG + SPL, and SHAM. Glucose tolerance tests were performed, and physical and biochemical parameters evaluated. Glucose-induced insulin secretion and protein expression (Glut2/glucokinase) were measured in isolated pancreatic islets. Pancreases were submitted to histological and immunohistochemical analyses, and vagus nerve neural activity was recorded. Results: The vagotomized group presented with reduced body weight, growth, and adiposity; high food intake; reduced plasma glucose and triglyceride levels; and insulin resistance. The association of SPL with the VAG surgery attenuated, or abolished, the effects of VAG and reduced glucose-induced insulin secretion and interleukin-1β area in β cells, in addition to lowering vagal activity. Conclusions: The absence of the spleen attenuated or blocked the effects of VAG on adiposity, triglycerides and glucose homeostasis, suggesting a synergistic effect of both on metabolism. The vagus nerve and spleen modulate the presence of interleukin-1β in β cells, possibly because of the reduction of glucose-induced insulin secretion, indicating a bidirectional flow between autonomous neural firing and the spleen, with repercussions for the endocrine pancreas.
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A high-fat diet induces obesity in mice, leading to insulin resistance, decreased mitochondrial function, and increased apoptosis in the hippocampus, which eventually result in memory loss. The present study investigated the effect of physical exercise on memory, hippocampal mitochondrial function, and apoptosis in mice with in insulin resistance caused by obesity due to high-fat diet. Mice were randomly divided into four groups: control (CON), control and exercise (CON + EX), high fat diet (HFD), and high fat diet and exercise (HFD + EX). After receiving a high-fat (60%) diet for 20 weeks to induce obesity, the animals were subjected to an exercise routine 6 times per week, for 12 weeks. The exercise duration and intensity gradually increased over 4-week intervals. Hippocampal memory was examined using the step-down avoidance task. Mitochondrial function and apoptosis were also examined in the hippocampus and dentate gyrus. We found that obesity owing to a high-fat diet induced insulin resistance and caused a decrease in memory function. Insulin resistance also caused a decrease in mitochondrial function in the hippocampus by reducing Ca2+ retention and O2, respiration, increasing the levels of H2O2, and Cyp-D, and mPTP opening. In addition, apoptosis in the hippocampus increased owing to decreased expression of Bcl-2 and increased expression of Bax, cytochrome c, and caspase-3 and TUNEL-positive cells. In contrast, physical exercise led to reduced insulin resistance, improved mitochondrial function, and reduced apoptosis in the hippocampus. The results suggest that physiological stimulations such as exercise improve hippocampal function and suppress apoptosis, potentially preventing the memory loss associated with obesity-induced insulin resistance.
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Background Obese, type two diabetics are at an increased risk for fracturing their limb bones in comparison to the general population. Phytoestrogens like as the soy isoflavone genistein have been shown to protect against bone loss. In this study, we tested the effects of genistein treatment on femurs of ob/ob mice, a model for obesity and type two diabetes mellitus. Methods Twenty six-week-old female mice were divided into obese (ob/ob) control, obese genistein-treated, lean (ob/+) control, and lean genistein-treated groups (n = 5 each). Treatment with genistein consisted of 600 mg genistein/kg diet. Control mice were given standard rodent chow. At the end of a four-week treatment period, bone histomorphometric and three-point bending properties were compared among groups. ResultsObese mice had larger bone areas (B.Ar.; P < 0.05) and total areas (Tt.Ar.; P < 0.05), but similar bone volume (B.Ar./Tt.Ar.; P > 0.05) of the proximal femoral epiphysis in comparison to lean mice. Treatment with genistein decreased Tt.Ar. and femur length, and increased ultimate force required to fracture the femur and the maximum deformation to failure (P < 0.05). Conclusions Genistein improves resistance to fracture from bending loads.
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Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to summarize the anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and present the potential health risks.
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Background: Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. Methods: In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Results: Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Conclusion: Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight.
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Background: -High fat diet (HFD) promotes endothelial dysfunction and pro-inflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces dysfunction of red blood cells (RBC), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC). Methods and results: -60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of MCP-1 bound to RBC, which in turn stimulated macrophage migration through an endothelial monolayer. Levels of RBC bound KC were also increased by HFD. These effects of HFD were abolished in DARC -/- mice. In RBC from HFD-fed wild-type and DARC -/- mice, levels of membrane cholesterol and phosphatidylserine externalization were increased, fostering RBC-macrophage inflammatory interactions and promoting macrophage phagocytosis in vitro. When labeled ex vivo and injected into control mice, RBC from HFD-fed mice exhibited ~3 fold increase in splenic uptake. Finally, RBC from HFD-fed mice induced increased macrophage adhesion to the endothelium when they were incubated with isolated aortic segments, indicating endothelial activation. Conclusions: -RBC dysfunction, analogous to endothelial dysfunction, occurs early during diet-induced obesity and may serve as a mediator of atherosclerosis. These findings may have implications for the pathogenesis of atherosclerosis in obesity, a worldwide epidemic.
High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Four week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42 g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14 weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS-1. These changes were accompanied by inflammatory (NFκB, JNK) and stress responses (p38 MAPK and CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice.
Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-α and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.