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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
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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 and phenotypic data from mice in all five groups were reported [24,25]. Mice fed an HFSD displayed obesity, hyperinsulinemia, hyperglycemia, and T2DM [24,25]. ...
... The metabolic and phenotypic data from mice in all five groups were reported [24,25]. Mice fed an HFSD displayed obesity, hyperinsulinemia, hyperglycemia, and T2DM [24,25]. Figure 1 illustrates the significant differences in plasma IL-6, chondrocyte MMP-13, and col10a expression in lean mice and mice fed an HFSD. Figure 2 displays immunofluorescence staining of MMP-13 and col10a in articular cartilage of the proximal tibia. ...
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Type 2 diabetes mellitus and osteoarthritis (OA) often present as comorbidities. We examined the role of plasma IL-6, chondrocyte MMP-13, and col10a expression in the development of OA in obese diabetic mice. We further investigated dietary genistein and exercise training as potential mitigators of OA. One hundred adult mice (50 females, 50 males) aged 6 weeks were randomized into 5 groups, including lean controls, obese diabetic controls, and obese diabetic mice treated with genistein, exercise training, and genistein plus exercise training. The obese diabetic state was induced by feeding the mice a high-fat, high-sugar diet. Genistein was incorporated into the diet at a concentration of 600 mg genistein/kg. Exercise training was performed on a treadmill and consisted of daily 30 min sessions at 12 m/min, 5 days/week for a 12-week period. After treatment, plasma was collected, and proximal tibias were removed for analysis. Plasma IL-6 and MMP-13 were elevated while col10a was reduced in obese diabetic mice in comparison to lean controls. Dietary genistein treatment reduced IL-6 and MMP-13 expression and increased col10a expression. Histological examination of articular cartilage showed reduced thickness of the uncalcified zones and proteoglycan content in the cartilage of diabetic mice in comparison to mice fed genistein. Exercise training had no significant effect. In conclusion, genistein (and not exercise training) attenuates OA by reducing IL-6 and MMP-13 expression in diabetic mice.
... The impacts of folate deficiency and the HFF diet on systemic immune responses were evaluated by the functions of splenocytes. Our results showed that C57BL/6 mice fed the HFF diet had significantly larger spleen compared to those fed a normal-fat diet, which was similar to another study [41]. The spleen is the largest peripheral lymphoid organ in the body, containing a large number of immune cells such as T and B cells that secret cytokines and modulate the systemic immune response. ...
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The prevalence of obesity and chronic kidney disease (CKD) is increasing simultaneously and rapidly worldwide. Our previous study showed that folate deficiency increased lipid accumulation and leptin production of adipocytes. Whether folate plays a role in CKD, particularly obesity-related nephropathy remains unclear. To investigate the effects of folate deficiency on CKD in diet-induced obese mice, four groups of male C57BL/6 mice were fed either a normal-fat diet (NF) with folate (NF+f); NF without folate (NF−f); high-fat high-fructose diet (HFF) with folate (HFF+f); or HFF without folate (HFF−f) for 12 months during the study. The results showed that HFF increased not only body weight, fasting blood glucose, total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, and blood pressure, but also cytokines levels, such as interleukin (IL)-2, interferon (IFN)-γ, IL-17A/F, IL-6, monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-β1. The indicators of kidney failure including urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), renal type I and IV collagen deposits and leptin content, and serum creatinine were also increased by HFF. Folate-deficient diets further elevated serum TC, LDL-cholesterol, IL-6, tumor necrosis factor (TNF)-α, MCP-1, TGF-β1, and leptin, but decreased IL-10 level, and thus exacerbated renal fibrosis. To investigate the possible mechanisms of folate deficiency on renal injury, phosphorylation of pro-fibrosis signaling molecules, including signal transducer and activator of transcription (STAT)3 and small mothers against decapentaplegic (Smad)2/3, were assayed. Both HFF and folate deficiency significantly increased the phosphorylation of STAT3 and Smad2/3, suggesting synergistic effects of HFF−f on chronic renal inflammation and fibrosis. In conclusion, the results demonstrated that folate deficiency might aggravate inflammatory status and enhance renal fibrosis.
... Genistein (4,5,7-trihydroxyisoflavone) is one of the main isoflavones distributed in the germ of soybean, fava bean, and alfalfa, whose physiological actions have been widely confirmed in humans and animals. In addition to improving immunity in mammals fed with high-carbohydrate and high-fat diets, genistein has been shown to exert effects on oxidative stress and lipid and glucose metabolism [26][27][28][29][30]. Additionally, studies have indicated that the control of obesity by diets rich in soy isoflavones is mainly achieved by reducing blood triglyceride (TG) and total cholesterol (T-CHO) in broiler breeder hens and rabbits [31,32]. ...
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A 56-day feeding trial was conducted to investigate the effects of genistein on growth, lipid metabolism, antioxidant capacity, and immunity of common carp fed with high-carbohydrate or high-fat diets. Five diets were used to feed fish: control diet (5% fat; CO), high-fat diet (11% fat; HF), high-carbohydrate diet (45% carbohydrate; HC), and HF or HC diet with 500 mg/kg genistein (FG or CG). Results showed that final body weight (FW) and specific growth rate (SGR) were significantly reduced, but the supplementation with genistein resulted in higher values of FW and SGR than the HF or HC group. Both high carbohydrate and high fat belong to high-energy diets, which may promote lipid deposition. Genistein obviously decreased liver triglyceride (TG) content and alleviated hepatic fat vacuolation in the HF and HC groups. The expression of lipid metabolism genes (cpt-1 and atgl) was markedly higher in the FG group than in the HF group. The lipid synthesis-related genes (fas, acc, and pparγ) were elevated in high-energy diets but recovered to the control level or reduced after genistein treatments. With respect to fatty acid transporter genes, fatp increased in the FG group, and cd36 increased in the CG group. Furthermore, the antioxidant and immune indexes, such as total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), acid phosphatase (ACP), and lysozyme (LZM) activities, were decreased, while malonate aldehyde (MDA) content, activities of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were enhanced in the HF and HC groups. The antioxidant and immunity values could be ameliorated by treatment with genistein. Moreover, the transcript levels of antioxidant-related genes (cat, gr, and nrf2) in the liver and anti-inflammatory factors (tgf-β and il-10) and lyz in the head kidney tissue were promoted, although the expression levels of proinflammatory factors (tnf-α and il-6) declined in the genistein supplementation group, which confirmed the antioxidant and immune-enhancing effects of genistein. Therefore, 500 mg/kg genistein could ameliorate the negative effects of high-energy diets on immunity.
... 43 It is possible that the effects could have been mediated by both T cells and other immune cells or in other tissues such as the spleen. [44][45][46][47][48][49][50] Hence, the absence of Tbet did not prevent the mice from developing obesity but prevented insulin resistance which resembles the phenotype observed in Th2-biased Balbc mice and metabolic healthy humans. [10][11][12] Similarly, deviation to Th2 responses or promoting Th2 biased responses in C57bl/6 mice by administering helminths or products derived from helminths led to improvement in symptoms of diabetes mellitus. ...
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Abstract Obesity and diabetes mellitus are common metabolic diseases prevalent worldwide. Mice are commonly used to study the pathogenesis of these two conditions. Obesity and diabetes mellitus are induced by administering a high‐fat diet in many studies although other diet‐induced models are also used. Several factors may influence the outcome of the studies done to study diet‐induced obesity in mice. The immune system plays a crucial role in the susceptibility of mice to develop obesity and metabolic disease. In this article, the reasons for differences in susceptibility to develop obesity and diabetes mellitus in mice in response to high‐fat‐diet feeding and the influence of immunological bias of the mice strain used in studies are evaluated. Mice strains that induce proinflammatory and Th1‐type immune responses are found to be susceptible to high‐fat‐diet‐induced obesity. A few studies which directly compared the effect of a high‐fat diet on obesity and diabetic phenotype in Th1‐ and Th2‐biased mice strains were briefly analyzed. Based on the observations, it is proposed that the liver and adipose tissue may respond differently to high‐fat‐diet feeding regimens in Th1‐ and Th2‐biased mice strains. For instance, in Th1‐biased mice, adipose tissue fat content was high both in the baseline as well as in response to a high‐fat diet whereas in the liver, it was found to be less. It can be inferred that the immune responses to diet‐induced models may provide insights into the pathogenesis of obesity and diabetes mellitus.
... The morphological state of the spleen depends on metabolic disorders in the body [16]. Previous studies have reported an association between obesity and an enlarged spleen or non-alcoholic fatty liver disease [3,27]. The spleen, as a peripheral organ of the immune system, reacts to any immunopathological process in the body, ensures erythrocyte homeostasis, participates in the effector phase of the humoral immune response and hematopoiesis, metabolism, and it is one of the main blood depots [14]. ...
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One of the most commoncharacteristics of obesity is the development of a systemic low-grade proinflammatory state in the entire body, including the immune organs. Spleen enlargement during diet-induced obesity contributes to the development of chronic inflammation. Melatonin due to immunomodulatory, antioxidant, and systemic metabolic rolesis proposed to be an effective candidate for anti-obesity therapy. As immune systems demonstrate pronounced circadian rhythmicity and immune cells have different types of melatonin receptors, a chronotherapeutic approach might be used to choose the most effective regimes of melatonin administration for the correction of obesity-provoked damage to the spleen. Thus, the main goal of our research was the analysis of the rats' spleen histophysiology during the development of high-calorie diet-inducedobesity (HCD) after administering melatonin daily at different times (morning or evening). Melatonin was administered by gavage for 7 weeks in the dose of 30 mg/kg 1 h before lights-off (HCD ZT11, M ZT11, evening), or 1 h after lights-on (HCD ZT01, M ZT01, morning). For assessment of the morpho-functional state of the spleen,the histopathological evaluation of red and white pulp in different zones of lymphoid follicles was implemented. It was observed that obesity development wasaccompaniedbyhyperemia and vessel dilatation in the red pulp; while in the white pulp notable deformation of germinal centers and destroyed borders between zones of lymphoid follicles were noticed.The HCD group demonstrated a decrease inthe relative amount of the white pulp, the crosssectional area of germinal centers, and the cross-sectional area of the marginal zone; whilethe increased relative amount of red pulp and marginal zone/germinal centers ratiowere detected compared with control. Melatonin administration to obese rats increases the relative amount of the white pulp (HCD ZT11 group), the cross-sectional area of germinal centers (HCD ZT01 and HCD ZT11 groups), and the cross-sectional area of the marginal zone (HCD ZT11 group), and decreasesmarginal zone/germinal centers ratio (HCD ZT01 group) in comparison with the HCD group.Also,it was demonstrated that a choice between the morning or evening regimes of the melatonin treatment did not affect the histophysiology of the spleen in rats receivingthe standard diet (M ZT01 and M ZT11 groups). These results indicate that melatonin can be considered to be a powerful potential therapeutic agent for the amelioration of obesity-induced changes in the spleen.
... As irregular food intake and the emerging metabolic disturbance often correlate with systemic inflammation, we hypothesized that a low-grade systemic inflammation may be triggered by AL feeding, leading to the development of a more severe form of arthritis. To search for differences between TRF and AL mice in the steady-state conditions of the immune system (corresponding to the state before arthritis induction), we measured spleen weight, which is considered an indicator of low-grade systemic inflammation (52,53). TRF reduced the average spleen weight (Figure 2A), and resulted in significant rhythmicity of daily weight changes ( Figure 2B; Supplementary ...
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Time restricted eating, the dietary approach limiting food intake to a maximal 10-hour period of daytime is considered beneficial in metabolic dysfunctions, such as obesity and diabetes. Rhythm of food intake and parallel changes in serum nutrient levels are also important entrainment signals for the circadian clock, particularly in tissues involved in metabolic regulation. As both the metabolic state and the circadian clock have large impact on immune functions, we investigated in mice whether time restricted feeding (TRF) affects systemic inflammatory potential. TRF slackened the symptoms in K/BxN serum-transfer arthritis, an experimental model of human autoimmune joint inflammation. Compared to ad libitum conditions TRF reduced the expression of inflammatory mediators in visceral adipose tissue, an integrator and coordinator of metabolic and inflammatory processes. Furthermore, TRF strengthened the oscillation of peripheral leukocyte counts and alongside decreased the pool of both marginated and tissue leukocytes. Our data suggest that the altered leukocyte distribution in TRF mice is related to the attenuated expression of adhesion molecules on the surface of neutrophils and monocytes. We propose that TRF modifies both rhythm and inflammatory potential of leukocytes which contribute to the milder reactivity of the immune system and therefore time-restricted eating could serve as an effective complementary tool in the therapy of autoinflammatory processes.
... MM cells typically reside within hematopoietic niches and are thought to hijack normal signalling pathways to support their growth 44 . In mice, the red pulp of the spleen is a common site of extramedullary haematopoiesis 34,45 , and expansion of both red and white pulp is observed in diet-induced splenomegaly 46 . Given that the spleen is a hospitable site for Vk*MYC cells to reside, it is possible that the increased splenic tumour burden in HFD mice may not be due to changes in metabolic signalling but rather an increased availability of MM niches resulting from HFD-induced splenomegaly. ...
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Multiple myeloma (MM) is an incurable haematological malignancy, caused by the uncontrolled proliferation of plasma cells within the bone marrow (BM). Obesity is a known risk factor for MM, however, few studies have investigated the potential of dietary intervention to prevent MM progression. Calorie restriction (CR) is associated with many health benefits including reduced cancer incidence and progression. To investigate if CR could reduce MM progression, dietary regimes [30% CR, normal chow diet (NCD), or high fat diet (HFD)] were initiated in C57BL/6J mice. Diet-induced changes were assessed, followed by inoculation of mice with Vk*MYC MM cells (Vk14451-GFP) at 16 weeks of age. Tumour progression was monitored by serum paraprotein, and at endpoint, BM and splenic tumour burden was analysed by flow cytometry. 30% CR promoted weight loss, improved glucose tolerance, increased BM adiposity and elevated serum adiponectin compared to NCD-fed mice. Despite these metabolic changes, CR had no significant effect on serum paraprotein levels. Furthermore, endpoint analysis found that dietary changes were insufficient to affect BM tumour burden, however, HFD resulted in an average two-fold increase in splenic tumour burden. Overall, these findings suggest diet-induced BM changes may not be key drivers of MM progression in the Vk14451-GFP transplant model of myeloma.
... The majority of preclinical studies of animal models with type 2 diabetes show that genistein significantly reduces circulating glucose concentrations (25,26,(29)(30)(31)(32)(33)(34)(35) and triglyceride concentrations (25,(30)(31)(32), in addition to improving insulin sensitivity (25,30,33,35), although effects on insulin concentrations and body mass were inconsistent. ...
Diabetes is the 8th leading cause of death in the world and the prevalence is rising in low-income countries. Cardiovascular diseases are the leading cause of death worldwide, especially for individuals with diabetes. While medications exist to treat symptoms of diabetes, lack of availability and high costs may deter their use by individuals with low incomes as well as those in low-income nations. Therefore, this systematic review was performed to determine whether genistein, a phytoestrogen found in soy products, could provide therapeutic benefits for individuals with diabetes. We searched PubMed and SCOPUS using the terms 'genistein', 'diabetes', and 'glucose' and identified 33 peer-reviewed articles that met our inclusion criteria. In general, preclinical studies demonstrated that genistein decreases body weight and circulating glucose and triglycerides concentrations while increasing insulin levels and insulin sensitivity. Genistein also delayed the onset of type 1 and type 2 diabetes. In contrast, clinical studies utilizing genistein generally reported no significant relationship between genistein and body mass, circulating glucose, A1C concentrations, or onset of type 1 diabetes. However, genistein was found to improve insulin sensitivity and serum triglyceride concentrations and delayed the onset of type 2 diabetes. In summary, preclinical and clinical studies suggest that genistein may help delay the onset of type 2 diabetes and improve several symptoms associated with the disease. Although additional research is required to confirm these findings, the results highlighted in this review provide some evidence that genistein may offer a natural approach to mitigating some of the complications associated with diabetes.
... To determine whether loss of SMC Notch2 had a systemic effect on physiological measures that can determine risk for cardiovascular disease, we measured BP, weight, serum glucose and cholesterol, as well as heart weight relative to mouse size (tibia length) as an indicator of cardiac hypertrophy and spleen weight as a rough indicator of systemic inflammation [21] (Table 1). There Notch2 deletion in vascular SMC in ApoE −/− mice. ...
Introduction: We previously identified Notch2 in smooth muscle cells (SMC) in human atherosclerosis and found that signaling via Notch2 suppressed human SMC proliferation. Thus, we tested whether loss of Notch2 in SMC would alter atherosclerotic plaque progression using a mouse model. Methods: Atherogenesis was examined at the brachiocephalic artery and aortic root in a vascular SMC null (inducible smooth muscle myosin heavy chain Cre) Notch2 strain on the ApoE-/- background. We measured plaque morphology and size, as well as lipid, inflammation, and smooth muscle actin content after Western diet. Results: We generated an inducible SMC Notch2 null on the ApoE-/- background. We observed ∼90% recombination efficiency with no detectable Notch2 in the SMC. Loss of SMC Notch2 did not significantly change plaque size, lipid content, necrotic core, or medial area. However, loss of SMC Notch2 reduced the contractile SMC in brachiocephalic artery lesions and increased inflammatory content in aortic root lesions after 6 weeks of Western diet. These changes were not present with loss of SMC Notch2 after 14 weeks of Western diet. Conclusions: Our data show that loss of SMC Notch2 does not significantly reduce atherosclerotic lesion formation, although in early stages of plaque formation there are changes in SMC and inflammation.
... It filters bacteria and viruses from the blood and serves as a home for circulatory lymphocytes and an antigen interaction site [6]. Diabetes and obesity-related chronic kidney disease are caused by functional and morphological changes in the spleen [7]. ...
Context: 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. Objective: This study evaluated the combined efficacy of melatonin and insulin in attenuation of lipopolysaccharide (LPS) caused inflammation, macrophage functional impairment, and oxidative stress in the spleen of diabetic mice. Materials and Methods: Multiple low doses of streptozotocin (50mg/kg B. wt.) were administered intraperitoneally to induce diabetes. Diabetes mice were divided into two sets. Set-1 contained control, diabetes, diabetes insulin (2IU/100g B.wt.) treated, diabetes melatonin (100µg/100g. B.wt.) treated, and diabetes melatonin and insulin treated groups of mice. In set II, the same number of groups as those of set I were given a single dose of LPS (50µg/mice) 24 hours before euthanization. Results and Discussion: 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. Conclusions: The present study may suggest a combinatorial approach in the therapeutic use of melatonin and insulin to improve such devastating conditions.
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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.
Genistein, a phytoestrogen that demonstrates bone‐protective properties, is currently being investigated as a treatment for a number of conditions that affect skeletal health, including type 2 diabetes. Type 2 diabetics have an elevated risk of developing fractures, particularly in bones of the lower limb. Type 2 diabetics also tend to be obese ‐ as many as 85% according to the World Health Organization. This study investigates the effects of genistein treatment on the properties of lower limb bones in obese, diabetic mice. Twenty mice of the ob/ob strain aged 6 weeks were randomly divided into two groups. One group received 600 mg/kg of genistein in their chow for 4 weeks. Comparisons of tibial midshafts show mice treated with genistein have significantly greater diameters and ratios of cortical bone to total tissue area ( than controls (P < 0.05). Evaluation of the proximal tibial growth plate reveals significantly decreased growth plate thickness in genistein‐treated mice, suggesting genistein affects endochondral ossification. Although these initial findings are promising, further study is needed to assess the effects of genistein on fracture risk in type 2 diabetics.
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.