الفهرس 
Energy Balance: The homeostatic systemOnly 14 pages are availabe for public view
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Abstract
Energy homeostasis is a balance between energy intake and
expenditure, which is controlled by a complex interplay between the
central nervous system and a number of other organs. Energy intake
is the amount of food and drink intake and absorption, while energy
expenditure is the energy expended through resting metabolic rate,
the thermic effect of food, thermoregulation and physical activity in
adults over a long period of time and another basal metabolism
(Guyenet and Schwartz, 2012 and Folgueira et al., 2014). When
energy intake exceeds energy expenditure positive energy balance
occurs, which leads to obesity. Negative energy balance is just the
opposite and results in weight loss (Zhan et al., 2013).
Obesity models were used for determining and understanding
the energy homeostasis of the body. Obesity results from an
imbalance between energy intake and output, which promotes
energy storage leading to increased gain in body weight and
accumulation of fats in the body (Ebbert et al., 2013 and
Arnoldussen et al., 2014). Various feedback mechanisms regulate
appetite, energy intake and expenditure to maintain energy
homeostasis. When these feedback mechanisms are altered, energy
balance is disturbed and body adiposity became unstable (Guyenet
and Schwartz, 2012 and Hall et al., 2015).
In high fat diet (HFD) models, hyperlipidemia is induced when
dietary lipid including cholesterol inhibits FA oxidation and
LDL.cholesterol (LDL.c) uptake. Lipids, such as triacylglycerol,deposit, especially in adipose tissue, causing hypertrophy and
hyperplasia, leading to high body fat deposition overall the body
and increase in body weight. HFD is also associated with metabolic
disturbance and endothelial dysfunction (Vanhoutte, 2012;
Hemlata et al., 2013 and Lee et al., 2014).
Triton WR-1339, a non-ionic detergent (oxyethylated tertiary
octylphenol formaldehyde polymer), is used as an inhibitor of
lipoprotein lipase (LPL) activity which blocks plasma lipolytic
activity leading to blocking the uptake of circulating , especially
triglyceride, by extrahepatic tissues and other peripheral tissues,
resulting in increased blood lipid concentration and increased
hepatic cholesterol synthesis, particularly by the increase in HMG
Co-A (3-hydroxy-3-methyl-glutaryl Co-A) reductase activity. Triton
WR-1339 has been used for screening natural or chemical
hypolipidemic drugs lipid metabolism, and also for investigating the
metabolic interrelationship between blood lipoproteins (Aziz et al.,
2009 and Adeneye, 2015).
Several studies have provided evidence that diet-induced obesity
leads to insulin resistance accompanied with obesity that is mainly
due to the presence of inflammation (Gregor and Hotamisligil,
2011 and Benzler et al., 2015).
Several studies have provided evidence on the efficacy of black
pepper and coffee as anti-obesity anti-hyperlipidemia agents. They
have also suggested that black pepper and coffee have
thermogenesis properties; however, the underlying mechanism is
still unclear.Until now researchers have uncovered all types of central and
peripheral regulation sites, hormones, peptides, receptors, and genes
involved in energy balance. Also, the mechanism of how all these
network systems is designed and connected together to continually
correct for positive and negative energy balance is unclear. So that,
the present study aimed to investigate the role of cAMP in obesity
since it is a key regulator of energy balance that connects the
complex central and peripheral control systems to achieve energy
balance and open hope to understand the mechanism of many
disturbances resulting from metabolism related to many diseases
especially that associated with obesity.
This study is based on the induction of obesity using mainly
HFD, in addition to triton-1339.
The study included 80 male albino rats divided into ten
groups (eight rats in each group) including control, High Fat Diet
(HFD), triton, HFD+triton, black pepper+HFD, black
pepper+HFD+triton, coffee+HFD, coffee+HFD+triton,
mixture+HFD and mixture+HFD+triton groups.
During the experimental period (16 weeks) food intake (FI)
was recorded every other day in each group, and the animals were
weighed twice weekly in all groups to determine BWG%, FER.
After the experimental period (16 weeks), blood and brain tissues
were collected for estimation of the following parameters:
1- Fasting blood glucose by spectrophotometer.
2- Plasma insulin by ELISA.3- Insulin resistance (HOMA-IR) which was calculated by the
product of the fasting concentrations of glucose (mg/dL) and
insulin (µU/mL) divided by 405.
4- Kidney function tests (serum urea and serum creatinine) by
spectrophotometer.
5- Liver function tests (serum ALT and serum AST) by
spectrophotometer.
6- Serum lipid profile and lipoprotein cholesterols by
spectrophotometer.
7- Brain neurotransmitters: norepinephrine, dopamine, and
serotonin by HPLC.
8- Brain and serum cyclic adenosine monophosphate by ELISA.
The results obtained can be summarized as follows:
1- The mean values of blood glucose and insulin were significantly
increased in HFD group, HFD+triton group, and triton group
when compared to control group. HFD- fed rats treated with
coffee, black pepper or their mixture had significant decreases in
blood glucose and insulin as compared to non-treated HFD
group. Similarly, HFD+ triton+ mixture had significant
decreases in blood glucose and insulin as compared to nontreated HFD group. Moreover, HFD+ triton+ black pepper and
HFD+ triton+ coffee treated groups had non-significant
decreases in blood glucose concomitant with significant
decreases in insulin as compared to non-treated HFD group.
2- The mean value of serum levels of the liver enzymes (AST and
ALT) and the kidney profile (urea and creatinine) weresignificantly increased in HFD group, HFD+triton group, and
triton group when compared to control group. Treatment with
black pepper, coffee, and their mixture improved the serum
ALT, urea, and creatinine by significantly decreased the mean
values of serum ALT, urea, and creatinine when compared to
HFD group. On the other hand, the present study showed that
treatment with black pepper, coffee, and their mixture in all
treated groups except in HFD+ triton + coffee group showed a
significant decrease in the mean value of serum AST compared
to HFD group; while HFD+ triton+ coffee group caused a
significant increase in the mean value of serum AST compared
to HFD group.
3- The mean value of serum levels of TG, VLDL, LDL-C and TC
were significantly increased in HFD group, HFD+triton group,
and triton group compared to control group, concomitant with a
significant increase of HDL in obese groups compared to
control. HFD-fed rats treated with coffee, black pepper and their
mixture had significant decreases in serum TC, TG, VLDL and
LDL-C concomitant with significant increases in serum HDL-C
as compared to HFD group. On the other hand, the HFD+ triton
group treated with coffee, black pepper and their mixture had
significant decreases in serum TC and LDL-C concomitant with
significant increases in serum HDL-C as compared to HFD
group; while there were non- significant decreases in serum TG
or VLDL as compared to HFD group.- The mean values of serum cAMP in the HFD group, HFD+triton
group, and triton group were significantly decreased compared
to the control group. On the other hand, surprisingly, the mean
values of brain cAMP in the HFD group, HFD+triton group, and
triton group were significantly increased compared to the control
group. Treatment with black pepper, coffee, or their mixture
caused significant increases in the mean values of serum cAMP
concomitant with significant decreases in the mean values of
brain cAMP when compared to HFD group.
5- The present data revealed that the concentration of brain
norepinephrine, dopamine and serotonin had significant
elevations in HFD group when compared to control group.
Moreover, the concentration of brain norepinephrine in HFD+
triton group and triton group had significant elevations when
compared to both the control and HFD groups. In addition,
dopamine concentration in HFD+ triton group had nonsignificant elevation when compared to HFD group and
significant elevation when compared to control group, while the
dopamine concentration in triton group had significant
elevations when compared to both the control and HFD groups.
However, the concentration of brain serotonin in HFD+ triton
group and triton group had significant decreases when compared
to both the control group and HFD group.
Concerning NE, the present data revealed that the mean values
of NE in HFD-fed rats (either injected with triton or not) treated
with black pepper, coffee and their mixture were significantlydecreased compared to HFD group; while the mean values of
NE in HFD+ black pepper, HFD+ coffee, HFD+ triton+ coffee
and HFD+ triton +mixture treated groups were non-significantly
increased compared to control group. In contrast, NE was
significantly increased in HFD+ mixture and HFD+ triton+
black pepper treated groups, compared to control group.
Concerning dopamine, The mean values of dopamine levels
in HFD+ coffee treated group and HFD+ triton+ coffee treated
group were significantly decreased compared to HFD group and
significantly increased compared to control group. Surprisingly,
the mean value of dopamine level in HFD+ black pepper was
significantly increased compared to both the HFD group and
control group. Moreover, the mean value of dopamine level in
HFD+ triton+ black pepper was non-significantly decreased
compared to HFD group and significantly increased compared to
control group. In contrast, the mean values of dopamine levels in
HFD+ mixture group and HFD+ triton+ mixture group were
significantly decreased compared to both HFD group and control
group.
Concerning serotonin, the present data revealed that the
mean values of serotonin in HFD-fed rats (either injected with
triton or not) treated with black pepper or coffee were
significantly increased compared to both HFD group and control
group. Moreover, the HFD+ mixture treated group had
significant elevations in serotonin levels compared to both HFD
group and control group, while the mean value of serotonin in HFD+ triton+ mixture treated group was non-significantly
decreased compared to HFD group and significantly increased
compared to control group.
6- The mean values of the FER, BMI, BWG% and organ weight
and fat pad as liver, lung, heart, pancreas, spleen, kidney, tests,
abdominal fat and adipose tissue were significantly increased in
HFD group and HFD+ triton group compared to the control
group. Treatment with black pepper, coffee, and their mixture
improved (FER), (BMI), (BWG%) and weights of organs (Liver,
Lung, Heart, Pancreas, Spleen, Kidney, Tests, Abdominal fat
and Adipose tissue) compared to HFD group, with the exception
that the heart weights in HFD rats injected with triton and treated
with coffee, was increased more than HFD group.
Hyperlipidemia induced by triton WR-1339 occurs via two
phases: Phase I: in which there is an increased hepatic cholesterol
biosynthesis through triton’s interference with the tissue uptake of
plasma lipids, while Phase II: involves triton’s interference with
cholesterol excretion and metabolism, in the same line, in high-fat
diet models, hyperlipidemia is induced when dietary lipid including
cholesterol inhibits FA oxidation and LDL cholesterol uptake. So
that, HFD is associated with metabolic disturbance, obesity, insulin
resistance, liver injury, atherosclerosis, endothelial dysfunction and
brain risk.
In this study, high blood glucose and insulin may be due to
hyperlipidemia and increased amount of free fatty acid which
directly affects insulin signaling, diminishes glucose uptake in muscles and adipose tissue, drives exaggerated triglyceride
synthesis and induces gluconeogenesis in the liver leading to
elevated levels of glucose and lipids which may lead to type-2
diabetes, insulin resistance, and metabolic syndrome.
In the current study, the significant increase in mean values of
liver and kidney functions in HFD and triton groups compared to
control. This is due to the fact that hyperlipidemia, abnormal lipid
metabolism and increased fatty acids lead to liver injury such as
non-alcoholic fatty liver and hepatic steatosis as well as renal injury.
These results were confirmed by a histopathological study, which
revealed that liver sections had lymphocytic infiltration in the portal
and periportal areas. The dilated sinusoids were also noticed. Other
sections showed microvesicular and macrovesicular patterns of fatty
infiltration. In some rats, disturbance of the hepatic architecture was
associated with foci of hepatocytes necrosis was seen.
This present study suggested that the negative correlation
between serum cAMP and brain cAMP may come back to the
adiposity negative feedback. The mechanism that underlying this
result is unclear.
High levels of brain cAMP in obese rats are supported by the
suggestion of that some variants in melanocortin 4 receptors
(MC4R) and hypothalamic leptin resistance and high leptin level in
the brain of obese leading to accumulation of intracellular cAMP.
Also, high leptin levels in the obese brain lead to failure to activate
PDE3B which is required for lowering intracellular cAMP level.
Contrarily, the low levels of serum cAMP in obese may be due to
the increase of free fatty acids and increased serum levels of mediators such as TNF-α, IL-1, IL-6, and NF-κB and reduced
PPAR-γ expression, resulting in an overall decrease of serum
cAMP. Also, obesity is associated with decreased serum BDNF
concentrations that its concentration positively correlated with
cAMP level leading to low serum cAMP level in obese.
Obese rats intake highly caloric diets due to high significant
brain NE than normal weight rats increased NE turnover in
peripheral tissues and elevated resting plasma norepinephrine levels,
high NE in the obese eliciting recruitment of BAT, including
increased and overexpression of UCP1 levels lead to both
hyperplasia and hypertrophy of BAT and cardiovascular disorders.
Also, these previous study investigates a positive correlation
between glucose and norepinephrine.
Dopamine levels are elevated in the brains of obese as
Dopamine1 receptor (DRD1) expression and its down regulator
cAMP-regulated phosphoprotein of 32 KDa (DARPP 32) were
increased, resulting in increased cAMP-PKA pathway but at the
same time Dopamine 2 receptor (DRD2) expression decreased, that
BMI correlated negatively with the measures of D2 receptors.
There are two oppose theories have different effects regard to
5-HT function in lipid and glucose metabolism. The first one
regarded that serotonin level increases in obesity and
pharmacological ”enzyme blocker”, blocking the production of
peripheral serotonin makes the brown fat more active and decrease
the body weight. The second one supports that serotonin used as an
anti-obesity target such as serotonin reuptake inhibitors (SRI) that
stimulate serotonin causing weight loss, suppressing food intake and feeling satiety, and the present study supports the two theories
suggested that hyperlipidemia may have more different pathways
that affected serotonin.
Treatment with black pepper, coffee, and their mixture
improved (FER), (BMI), (BWG%) and feed intake.
Treatment with black pepper, coffee, or their mixture
improved glucose and insulin. Coffee has also improved blood
glucose level and glucose homeostasis, which may be due to the
inhibition of adenosine receptors lead to increase cAMP. Moreover,
coffee and black pepper stimulate lipid metabolism in HED-induced
obese rats, which is attributable to fat mobilization from adipose
tissue, decreases the serum levels of cholesterol and triglycerides
and increases the thermogenic response and energy expenditure.
Supplementations with black pepper, coffee, and their mixture
have also improved the serum ALT, AST (except for coffee + triton
group) and kidney urea and creatinine levels. These findings were
confirmed by histopathology where the histopathological
investigation of liver sections of obese rats treated with black
pepper showed the architecture of the hepatic lobules to be like a
normal liver. Histopathological examination of liver sections of
obese rats treated with coffee showed normal hepatic lobules
structure which may be associated with few microvesicular patterns
of fatty infiltration.