ArticlePDF AvailableLiterature Review

Beneficial effects of L-arginine on reducing obesity: Potential mechanisms and important implications for human health

Authors:

Abstract and Figures

Over the past 20 years, growing interest in the biochemistry, nutrition, and pharmacology of L-arginine has led to extensive studies to explore its nutritional and therapeutic roles in treating and preventing human metabolic disorders. Emerging evidence shows that dietary L-arginine supplementation reduces adiposity in genetically obese rats, diet-induced obese rats, finishing pigs, and obese human subjects with Type-2 diabetes mellitus. The mechanisms responsible for the beneficial effects of L-arginine are likely complex, but ultimately involve altering the balance of energy intake and expenditure in favor of fat loss or reduced growth of white adipose tissue. Recent studies indicate that L-arginine supplementation stimulates mitochondrial biogenesis and brown adipose tissue development possibly through the enhanced synthesis of cell-signaling molecules (e.g., nitric oxide, carbon monoxide, polyamines, cGMP, and cAMP) as well as the increased expression of genes that promote whole-body oxidation of energy substrates (e.g., glucose and fatty acids) Thus, L-arginine holds great promise as a safe and cost-effective nutrient to reduce adiposity, increase muscle mass, and improve the metabolic profile in animals and humans.
Content may be subject to copyright.
INVITED REVIEW
Beneficial effects of L-arginine on reducing obesity: potential
mechanisms and important implications for human health
Jason R. McKnight M. Carey Satterfield Wenjuan S. Jobgen
Stephen B. Smith Thomas E. Spencer Cynthia J. Meininger
Catherine J. McNeal Guoyao Wu
Received: 8 March 2010 / Accepted: 9 April 2010 / Published online: 1 May 2010
!Springer-Verlag 2010
Abstract Over the past 20 years, growing interest in the
biochemistry, nutrition, and pharmacology of L-arginine has
led to extensive studies to explore its nutritional and ther-
apeutic roles in treating and preventing human metabolic
disorders. Emerging evidence shows that dietary L-arginine
supplementation reduces adiposity in genetically obese rats,
diet-induced obese rats, finishing pigs, and obese human
subjects with Type-2 diabetes mellitus. The mechanisms
responsible for the beneficial effects of L-arginine are likely
complex, but ultimately involve altering the balance of
energy intake and expenditure in favor of fat loss or reduced
growth of white adipose tissue. Recent studies indicate that
L-arginine supplementation stimulates mitochondrial bio-
genesis and brown adipose tissue development possibly
through the enhanced synthesis of cell-signaling molecules
(e.g., nitric oxide, carbon monoxide, polyamines, cGMP,
and cAMP) as well as the increased expression of genes
that promote whole-body oxidation of energy substrates
(e.g., glucose and fatty acids) Thus, L-arginine holds great
promise as a safe and cost-effective nutrient to reduce
adiposity, increase muscle mass, and improve the metabolic
profile in animals and humans.
Keywords Arginine !Fat metabolism !
Brown adipose tissue !NO
Abbreviations
ACC Acetyl-CoA carboxylase
AMPK AMP-activated protein kinase
Arg L-Arginine
BAT Brown adipose tissue
CPT-1 Carnitine palmitoyl transferase-1
DIO Diet-induced obese
GC Guanylyl cyclase
LCFA Long-chain fatty acid
NO Nitric oxide
NOS Nitric oxide synthase
PGC-1aPeroxisome proliferator-activated receptor c
coactivator-1a
UPC1 Uncoupling protein-1
WAT White adipose tissue
ZDF Zucker diabetic fatty
Introduction
Obesity is a major health problem in North America,
Europe, and many developing nations (CDC 2009; WHO
2009). For example, nearly 1 billion adults worldwide are
overweight and at least 300 million are obese (WHO 2009).
In the United States alone, 35% of the population is obese,
and approximately two-thirds of the population is
J. R. McKnight !M. C. Satterfield !W. S. Jobgen !
S. B. Smith !T. E. Spencer !G. Wu (&)
Department of Animal Science, Faculty of Nutrition,
Texas A&M University, College Station, TX 77843, USA
e-mail: g-wu@tamu.edu
C. J. Meininger !G. Wu
Department of Systems Biology and Translational Medicine,
Texas A&M Health Science Center, College Station,
TX 77843, USA
C. J. McNeal
Department of Internal Medicine, Scott & White Healthcare,
Temple, TX 76508, USA
C. J. McNeal
Department of Pediatrics, Scott & White Healthcare,
Temple, TX 76508, USA
123
Amino Acids (2010) 39:349–357
DOI 10.1007/s00726-010-0598-z
overweight (Flegal et al. 2010). Excess body fat is stored
primarily in white adipose tissue (WAT). Although obesity
is recognized as a leading risk factor for insulin resistance,
Type-2 diabetes, atherosclerosis, stroke, hypertension, and
some types of cancer (including colon and breast cancers),
there are few medications for treating this chronic disease
(Pi-Sunyer 2003).
Growing evidence from animal studies indicates that
physiological levels of L-arginine (Arg) promote the oxi-
dation of glucose and long-chain fatty acids (LCFA), while
decreasing de novo synthesis of glucose and triacylglyce-
rols (Jobgen et al. 2009a; Wu et al. 2009). Additionally,
Arg supplementation increases lipolysis and inhibits
lipogenesis by modulating the expression and function of
key enzymes involved in anti-oxidative response and fat
metabolism in insulin-sensitive tissues (Jobgen et al.
2009b). Nitric oxide (NO), which is synthesized from Arg
by NO synthase (NOS) (Wu and Morris 1998), participates
in multiple cell-signaling pathways and, therefore, regu-
lates the metabolism of energy substrates in a cell- and
tissue-dependent manner (Jobgen et al. 2006).
In view of the important progress in Arg research, the
objectives of this review are to (1) highlight recent major
findings from animal models and human subjects regarding
anti-obesity effects of Arg; and (2) propose cellular and
molecular mechanisms mediating Arg effects. These
mechanisms may include the stimulation of mitochondrial
biogenesis and brown adipose tissue (BAT) development,
as well as the regulation of gene expression and metabolic
pathways.
Anti-obesity effects of Arg on animals and humans
Studies with rats
A novel anti-obesity effect of Arg was observed by Fu et al.
(2005) in a seminal study involving chronic Arg supple-
mentation to prevent endothelial dysfunction in adult
Zucker diabetic fatty (ZDF) rats (an animal model of Type-
2 diabetes mellitus). Beginning on week 4 of supplemen-
tation, Arg-treated rats (which received drinking water
containing 1.51% L-Arg-HCl) began to lose white fat mass
when compared with alanine-supplemented rats (isonitr-
ogenous control) despite similar food intake between the
two groups of obese animals. At the end of a 10-week
period of supplementation, epididymal and retroperitoneal
fat weights in Arg-treated rats were 28 and 46% lower,
respectively, when compared with the control group (Fu
et al. 2005). Similarly, dietary supplementation with either
Arg (0.24% L-Arg-HCl in drinking water) or watermelon
juice (0.2% L-citrulline plus Arg in drinking water) for
4 weeks reduced adiposity and improved endothelium-
dependent relaxation in adult ZDF rats (Wu et al. 2007b).
More recently, Jobgen et al. (2009a) reported that Arg
supplementation (free access to drinking water containing
1.51% Arg-HCl) for 12 weeks substantially reduced WAT
in diet-induced obese (DIO) rats (Fig. 1) without altering
intramuscular lipid content. Interestingly, Arg supplemen-
tation decreased the size of white adipocytes (Fig. 2) but
had no effect on their numbers (Jobgen et al. 2009a).
Additionally, the long-term Arg treatment increased skel-
etal muscle-weight by 12% and the whole-body disposal of
glucose by 14% without affecting serum levels of insulin,
adiponectin, growth hormone, corticosterone, or thyroid
hormones (Jobgen et al. 2009a). Furthermore, Arg
enhanced BAT mass in both ZDF rats (Wu et al. 2007b)
and DIO rats (Fig. 1), underscoring a novel role for Arg in
BAT growth and development.
Studies with pigs
The pig is both a useful animal model in biomedical
research and an agriculturally important species for meat
production (Deng et al. 2009; Elango et al. 2009; Suryawan
et al. 2009; Yin et al. 2009). A major issue in swine pro-
duction is that excessive amounts of subcutaneous WAT
(e.g., backfat) are naturally deposited in market-weight
pigs fed a conventional finishing diet (Mersmann and
Smith 2005). Tan et al. (2009) reported that supplementing
1% Arg to the diet of 110-day-old barrows for 60 days
reduced serum triglyceride levels by 20% and whole-body
fat content by 11%, while increasing whole-body skeletal-
muscle content by 5.5%. The effects of Arg on reducing
lipids and improving the efficiency of protein deposition in
finishing pigs were also detected by the metabolomic
analysis of serum samples (He et al. 2009). Unexpectedly,
intramuscular lipid content was 70% greater in Arg-
supplemented than in control pigs (Tan et al. 2009), indi-
cating that lipid metabolism and its regulation vary with
the anatomical location of WAT. Because muscle lipid
represents \3% of carcass fats, it has little impact on
whole-body lipid content in Arg-supplemented pigs (Tan
et al. 2009). Thus, supplementing Arg to finishing pigs
favorably reduced overall body white fat accretion,
enhanced muscle gain, and improved the metabolic profile.
Studies with humans
Multiple studies have evaluated the effect of Arg supple-
mentation on endothelial function in adult human subjects,
which have been summarized by us (Wu and Meininger
2000) and others (Yongyi et al. 2009). However, only one
clinical trial has been published regarding the specific
effect of Arg on adiposity in humans (Lucotti et al. 2006).
This was a 21-day randomized, placebo-controlled trial in
350 J. R. McKnight et al.
123
33 hospitalized middle-aged, obese (mean body mass
index =39.1 ±0.5 kg/m
2
) subjects with diet-controlled
Type-2 diabetes mellitus. During the study period, each
patient received a low-calorie diet (1,000 kcal/day) and a
regular exercise-training program (45 min twice a day for
5 days/week). They were randomized to 8.3 g Arg/day
(approximately 80 mg/kg body weight per day) or placebo.
This dose of Arg is equivalent to that for DIO rats (Jobgen
et al. 2009a) and finishing pigs (Tan et al. 2009). As
expected from the hypocaloric diet, both groups of subjects
exhibited reductions in (1) body weight (3.0 vs. 3.7 kg); (2)
fat mass (3.0 vs. 2.1 kg); (3) waist circumference (8.3 vs.
3.2 cm); and (4) circulating levels of glucose (3.2 vs.
1.8 mmol/L), fructosamine (54 vs. 23 lmol/L), and insulin
(8.2 vs. 3.0 mU/L). Moreover, increases in antioxidant
capacity and circulating levels of adiponectin were
observed for these patients. Importantly, all improvements
were significantly greater (Pvalues \0.0001 for most
variables) in the Arg group than in the placebo group.
Additionally, over the 3-week period of study, fat-free
mass was maintained in the arginine group but reduced by
1.6 kg in the placebo group. Notably, fat mass accounted
for 100% of the weight loss in the Arg group (without any
loss of fat-free mass) whereas the loss of fat-free mass
accounted for 43% of the total weight loss in the placebo
group. Thus, Arg supplementation to obese subjects pro-
moted fat reduction and spared lean body mass during
weight loss. Pediatric obesity is of particular concern in the
healthcare system, yet no studies to date have evaluated the
use of Arg for weight management in this population.
Potential mechanisms for Arg to reduce adiposity
Expression of genes
It is now known that amino acids can regulate expression
of genes in diverse cell types, including myocytes, adipo-
cytes, and hepatocytes (Palii et al. 2009; Tan et al. 2010;
Wang et al. 2009a,b,c). Using the microarray analysis
technique and the DIO rat model, Jobgen et al. (2009b)
reported that dietary Arg supplementation affected
expression of many genes in WAT. Of particular interest,
high-fat feeding decreased mRNA levels for lipogenic
enzymes, AMP-activated protein kinase (AMPK), glucose
transporters, heme oxygenase 3, glutathione synthetase,
Fig. 1 Beneficial effects of dietary L-arginine supplementation on
diet-induced obese rats. Data (mean ±SEM n=8) are adapted from
Jobgen et al. (2009a). After a 15-week period of low-fat or high-fat
feeding, rats continued to receive their respective diets and either
1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) in
drinking water for 12 weeks. Whole-body glucose disposal was
assessed by oral glucose tolerance test at the end of 10-week
supplementation, and area under the curve (AUC) was calculated. All
other variables were determined at the end of 12 week supplemen-
tation. Adiposity index is the sum of major fat pads (retroperitoneal,
mesenteric, epididymal, and subcutaneous adipose tissues) divided by
body weight
0
5
10
15
20
25
30
35
20 40 60 80 100 120 140 160
Adipocyte size (µm)
Adipocyte size distribution (%)
LF-Ala
LF-Arg
HF-Ala
HF-Arg
Fig. 2 Size distribution of adipocytes from retroperitoneal adipose
tissue (white fat) of rats. After a 15-week period of low-fat (LF) or
high-fat (HF) feeding, rats continued to receive their respective diets
and either 1.51% L-arginine-HCl (Arg) or 2.55% L-alanine (Ala,
isonitrogenous control) in drinking water for 12 weeks (Jobgen et al.
2009a). At the end of the 12-week period of L-arginine/L-alanine
supplementation, retroperitoneal adipose tissue was dissected to
determine adipocyte size (Jobgen et al. 2009a). Data are expressed as
mean ±SEM (n=8)
)mµ(setycopidaforetemaiD
P-value 45 55 65 75 85 95 105 11 5 125 135 145
Diet 0.13 0.005 0.002 0.001 0.052 0.51 0.001 0.0005 0.015 0.086 0.13
AA 0.13 0.020 0.003 0.004 0.23 0.16 0.001 0.0005 0.14 0.62 0.021
Diet x AA 0.19 0.056 0.016 0.14 0.052 0.011 0.050 0.17 0.60 0.80 0.21
P values for treatment effects
Arginine and obesity treatment 351
123
superoxide dismutase 3, peroxiredoxin 5, glutathione per-
oxidase 3, and stress-induced protein, while increasing
expression of carboxypeptidase-A, peroxisome prolifera-
tor-activated receptor (PPAR)-a, caspase 2, caveolin 3, and
diacylglycerol kinase. In contrast, Arg supplementation
reduced mRNA levels for fatty acid-binding protein 1,
glycogenin, protein phosphatase 1B, caspases 1 and 2, and
hepatic lipase, but increased expression of PPARc, heme
oxygenase 3, glutathione synthetase, insulin-like growth
factor II, sphingosine-1-phosphate receptor, and stress-
induced protein. Biochemical analysis revealed that Arg
supplementation prevented oxidative stress in WAT, skel-
etal muscle and livers of obese rats (Jobgen et al. 2009b)
and finishing pigs (Ma et al. 2010). Collectively, these
results indicate that Arg beneficially modulates gene
expression to enhance energy-substrate oxidation and
reduce white fat accretion in insulin-sensitive tissues.
Gene expression in WAT differed between DIO rats
(Jobgen et al. 2009b) and ZDF rats (Fu et al. 2005) in
response to dietary Arg supplementation. This may be
explained, in part, by marked differences in plasma con-
centrations of metabolites (e.g., amino acids, glucose and
fatty acids) and hormones (e.g., insulin and leptin) between
these two animal models, which may affect gene expres-
sion in mammalian cells (Flynn et al. 2009; Palii et al.
2009). Interestingly, Arg enhanced expression of key genes
for fatty acid oxidation [AMPK, NOS-1, and PPARc
coactivator-1a(PGC1a)] in WAT of ZDF rats (Fu et al.
2005), but had no effect on AMPK or NOS-1 and even
decreased PGC1aexpression in WAT of DIO rats (Jobgen
et al. 2009b). In contrast, Arg promoted expression of
lipogenic genes (including malic enzyme 1 and PPARc)
and reduced expression of glycogenin (the physiological
primer for glycogen synthesis) in WAT of DIO rats, but not
in ZDF rats. Because there is little synthesis of fatty acids
in WAT of adult rats due to the absence of acetyl-CoA
carboxylase (ACC) activity (Jobgen et al. 2006), the
increased expression of malic enzyme 1 and fatty acid
synthase in WAT of DIO rats may represent only a phys-
iological response to dietary manipulation. However,
increased expression of PPARc, which stimulates differ-
entiation and proliferation of preadipocytes (Chung et al.
2005), may enhance lipogenesis in intramuscular adipose
tissue and, therefore, intramuscular lipids (Tan et al. 2009).
Mitochondrial biogenesis
The mitochondrion is the major organelle for complete
oxidation of energy substrates in all cells except for
mammalian red blood cells (Jobgen et al. 2006). Approx-
imately 20% of cellular proteins regulate mitochondrial
formation and growth (Nisoli et al. 2008). It is now known
that PGC-1ais the master regulator of mitochondrial
biogenesis (Lehman et al. 2000; Puigserver et al. 1998; Wu
et al. 1999) and its expression is influenced by NO (Fu
et al. 2005). In turn, PGC-1astimulates expression of key
genes involved in mitochondrial biogenesis, including
nuclear respiratory factors 1 and 2, as well as PPARa
(Table 1). Studies with eNOS knockout mice and cell
cultures have shown that endogenous NO has an obligatory
role in the mitochondrial biogenesis, oxidation, and
remodeling of animal cells through the generation of
cGMP (Nisoli et al. 2003,2004). This conclusion is sup-
ported by growing evidence from work with cold-accli-
mated rodents (Petrovic
´et al. 2008a, b,2010), exercising
rats (Wadley and McConell 2007), and cultured cells
(McConell et al. 2009). Furthermore, Arg-derived poly-
amines are necessary for cell proliferation and differenti-
ation as well as mitochondrial function and integrity (Flynn
et al. 2009; Wu et al. 2009).
BAT development and thermogenesis
Brown adipose tissue is responsible primarily for non-
shivering thermogenesis in mammals (e.g., sheep, rats, and
humans) (Himmshagen 1990). Distinct from other tissues,
BAT contains very high quantities of uncoupling protein-1
(UCP1). Mitochondrial UCP1, which is localized exclu-
sively in brown adipocytes of BAT (Nisoli et al. 2003),
uncouples ATP synthesis from the oxidative process to
generate heat (Cannon and Nedergaard 2004). Of particular
interest, BAT produces 150–300 times more heat per kg
tissue than non-BAT organs (Power 1989). Excitingly, new
evidence shows that functional BAT exists in adult humans
(Cypess et al. 2009; Virtanen et al. 2009). In addition, BAT
activity is reduced in adult overweight or obese humans
and is positively correlated with resting metabolic rate (van
Marken Lichtenbelt et al. 2009). Furthermore, under cer-
tain conditions (e.g., increases in NO production and PGC-
1aexpression), white adipocytes may be converted into
brown adipocytes that express high levels of UCP-1 (Nisoli
and Carruba 2004).
NO has long been known to play an important role in
heat production and thermoregulation in mammals
(Scammell et al. 1996). It is now clear that protein kinase
G, a target protein for NO, controls BAT cell differentia-
tion and mitochondrial biogenesis (Haas et al. 2009). Thus,
inhibition of NO synthesis reduces blood flow to BAT (De
Luca et al. 1995), BAT development (Petrovic
´et al. 2005,
2008a,b; Saha et al. 1996), and cold-induced thermogen-
esis in rats (De Luca et al. 1995; Kamerman et al. 2003;
Saha et al. 1996). The recent discovery that Arg supple-
mentation increased amounts of BAT in fetal lambs (Sat-
terfield et al. 2009), DIO rats (Jobgen et al. 2009b), ZDF
rats (Wu et al. 2007a,b), and cold-acclimated rats (Petrovic
´
et al. 2010) raises an expectation that this nutritional
352 J. R. McKnight et al.
123
approach may provide a new means to stimulate physio-
logical thermogenesis and reduce white fat accretion in
animals and humans.
Cell signaling and metabolism
Effects of Arg on cell metabolism appear to be mediated
partially by NO and other metabolites (Eklou-Lawson et al.
2009; Gaudiot et al. 1998; Gouill et al. 2007). The con-
version of Arg to NO by NOS requires NADPH, thereby
creating another possible explanation for how Arg increases
glucose utilization through the pentose pathway and cellular
redox state (Phang et al. 2008). NO stimulates blood flow to
organs (e.g., the brain, skeletal muscle, cardiac tissue, small
intestine, and kidney), which allows for greater uptake of
energy substrates (e.g., glucose and LCFA) by for oxidation
to CO
2
and water (Jobgen et al. 2006). Additionally,
physiological levels of NO up-regulate the activity of car-
nitine palmitoyl transferase-1 (CPT-1; the mitochondrial
transporter of LCFA) and the expression of glucose trans-
porter 4 in hepatocytes (Garcia-Villafranca et al. 2003) and
skeletal muscle (Lira et al. 2007), respectively. This would
result in increased whole-body oxidation of both LCFA and
glucose via the mitochondrial Krebs cycle and electron
transport system. Furthermore, spermine and spermidine
(formed from Arg) may increase oxidation of LCFA and
glucose by maintaining mitochondrial function and integ-
rity in cells (Madsen et al. 1996).
Physiological levels of Arg increase the production of not
only NO but also carbon monoxide (CO) from diverse cell
types (Li et al. 2009). These two gaseous molecules activate
guanylyl cyclase, thereby increasing the production of
cGMP. The cGMP-dependent protein kinase phosphorylates
ACC, thereby reducing the conversion of acetyl-CoA to
Table 1 Key proteins in mitochondrial biogenesis, brown adipocyte development, and metabolism of energy substrates in animal cells and
tissues
Gene Functions
NO and CO synthesis
NOS-1, 2, 3 NOS-1 (nNOS) is a constitutive isoform of NOS that synthesizes NO from Arg in skeletal muscle, white adipose tissue, BAT,
and liver. NOS-2 (iNOS) is an inducible isoform of NOS that synthesizes NO from Arg in response to cytokines and other
inflammatory agents. NOS-3 (eNOS) is a constitutive isoform of NOS that synthesizes NO from Arg in endothelial cells,
skeletal muscle, heart, white adipose tissue, BAT, and liver. Among animal tissues, NOS-3 is most abundant in BAT
HO-1, 2, 3 Heme oxygenase (HO) generates CO from heme. HO-1 is highly inducible by oxidants, hypoxia and inflammatory cytokines in
diverse cell types. HO-2 is constitutively expressed in diverse cell types. HO-3 is expressed in white adipose tissue and skeletal
muscle where CO regulates oxidation of fatty acids and glucose
Mitochondrial biogenesis and BAT development
PGC-1aA master regulator of mitochondrial biogenesis and BAT development
NRF-1, 2, 3 Regulators and markers of mitochondrial biogenesis
PPARaA transcription factor that regulates cellular differentiation, development, and metabolism. It is highly expressed in hepatocytes
and skeletal muscle
mtTFA A mitochondrial transcription factor and a marker of mitochondrial biogenesis
Cytochrome
c
An enzyme of the mitochondrial respiratory chain and a marker of mitochondrial biogenesis
UCP-1 A unique protein in mitochondria of BAT which uncouples ATP synthesis from substrate oxidation
VEGF A key regulator of endothelial cell proliferation and angiogenesis in blood vessels and BAT
Metabolism of fatty acids and glucose
AMPKaA key regulator of (a) oxidation of energy substrates, (b) gluconeogenesis, and (c) fat synthesis
FAS An enzyme involved in the synthesis of fatty acids from glucose and amino acids
ACC-1, 2 ACC-1 is a major isoform of ACC in lipogenic tissues where it converts acetyl-CoA into malonyl-CoA in fatty acid synthesis.
ACC-2 is the predominant isoform of ACC in oxidative tissues (e.g., liver, muscle, and BAT) where it converts acetyl-CoA
into malonyl-CoA, an inhibitor of LCFA-CoA transport from cytoplasm into mitochondria. Phosphorylation of ACC reduces
its activity
SREBP-1c A key regulator of fatty acid and glucose synthesis in liver
HSL A key regulator of lipolysis in tissues, particularly white adipose tissue, BAT, and muscle
GAPDH An enzyme of the glycolysis pathway. It is often used to normalize gene expression in cells
Expression of the listed genes in cells and tissues may be altered by dietary L-arginine supplementation
ACC acetyl-CoA carboxylase, AMPK AMP-activated protein kinase, BAT brown adipose tissue, FAS fatty acid synthase, GAPDH glycer-
aldehyde-3-phosphate dehydrogenase, HSL hormone-sensitive lipase, mtTFA mitochondrial transcription factor A, NOS nitric oxide synthase,
NRF nuclear respiration factor, PGC-1aperoxisome proliferator activator receptor ccoactivator-1a,PPARaperoxisome proliferator activator
receptor-a,SREBP-1c sterol regulatory element-binding protein-1c, UCP uncoupling protein, VEGF vascular endothelial growth factor
Arginine and obesity treatment 353
123
malonyl-CoA, which is both an intermediate of the fatty acid
synthesis pathway and an inhibitor of CPT-I (Jobgen et al.
2006). By decreasing malonyl-CoA concentration, fatty
acid synthesis is inhibited while CPT-1 remains active to
promote the transport of LCFA from cytoplasm into mito-
chondria for oxidation. Additionally, NO enhances AMPK
activity by both increasing gene expression and AMPK
phosphorylation to (1) decrease glycerol-6-phosphate acyl-
transferase activity and thus triacylglycerol synthesis; (2)
down-regulate sterol regulatory element-binding protein 1c
(SREBP-1c) and thus fatty acid synthesis; and (3) stimulate
the conversion of glucose to pyruvate and the subsequent
complete oxidation of pyruvate via the Kreb cycle (Jobgen
et al. 2006; Lira et al. 2007). Thus, physiological levels of
NO and CO stimulate the oxidation of both LCFA and
glucose in insulin-sensitive tissues (Jobgen et al. 2006;
Fig. 3). Additionally, we found that dietary Arg supple-
mentation increased cAMP concentrations in WAT, BAT,
skeletal muscle, and livers of adult rats without altering
AMP:ATP ratios (Table 2). Because cAMP activates hor-
mone-sensitive lipase (Kersten 2001), an increase in cAMP
is another mediator of enhanced lipolysis in the adipose
tissue of Arg-supplemented rats.
Implications of Arg supplementation for human health
Obesity in humans and animals results from a chronic
imbalance between energy intake and expenditure. Results
of both animal and human studies indicate that Arg sup-
plementation may be a novel therapy for obesity and the
metabolic syndrome, acting via decreased plasma levels of
glucose, homocysteine, fatty acids, dimethylarginines, and
triglycerides, as well as improved whole-body insulin
sensitivity (Jobgen et al. 2009a; Kohli et al. 2004; Lucotti
et al. 2006; Mendez and Balderas 2001; Wu et al. 2007b).
Notably, an anabolic effect of Arg on muscle gain in adult
rats (Jobgen et al. 2009a) and finishing pigs (Tan et al.
2009) is achieved independent of changes in serum con-
centrations of insulin or growth hormone. This finding
indicates that dietary Arg supplementation enhances insu-
lin sensitivity and amplifies its signaling mechanisms on
protein synthesis (Yao et al. 2008) as well as the metabo-
lism of glucose and fatty acids (Jobgen et al. 2006). Thus,
Arg supplementation regulates the repartitioning of dietary
energy to favor muscle over fat gain in the body. Based on
the fact that protein intake by adult humans (0.8 g/kg body
weight per day) is approximately 13% of that for adult rats
and finishing pigs (6.2 and 6.0 g/kg body weight per day,
respectively) (Wu et al. 2007a), supplemental Arg doses of
950 and 365 mg/kg body weight per day for adult rats
(Jobgen et al. 2009a) and finishing pigs (Tan et al. 2009)
are equivalent to 85 (50–120) mg Arg/kg body weight per
day for adult humans. These amounts of Arg are physio-
logically attainable when the human diet is supplemented
with synthetic Arg.
Arg is stable under sterilization conditions (e.g., high
temperature and high pressure) and is not toxic to mam-
malian cells (Wu 2009). Therefore, multiple studies in both
animals and humans conclude that there are no safety
concerns regarding Arg supplementation at an appropriate
dose and chemical form (Bo
¨ger and Bode-Bo
¨ger 2001;
Mendez and Balderas 2001; Wu et al. 2009). Results of the
third National Health and Nutrition Examination Survey, a
program of studies designed to assess the health and
nutritional status of adults and children in the United
States, indicate that mean Arg intake for the US adult
population is 4.4 g/day, with 25, 20, and 10% of people
consuming \2.6 (suboptimal), 5–7.5, and [7.5 g/day,
respectively (King et al. 2008). Thus, large numbers of
adults do not have adequate Arg intake from diets to
maintain optimal metabolic pathways (e.g., syntheses of
0
0.5
1
1.5
2
2.5
3
3.5
4
05
30
nmol/2h per g tissue
Skeletal muscle tissue
Oleic acid oxidation
D
a
b
c
0
0.5
1
1.5
2
2.5
30
nmol/2h per g tissue
Adipose tissue
Oleic acid oxidation
C
c
b
a
0
200
400
600
800
1000
1200
1400
30
nmol/2h per g tissue
CO Donor ( M) CO Donor ( M)
Adipose tissue
Glucose oxidation
c
b
a
0
5
10
15
20
25
30
35
40
45
05
05 0 530
nmol/2h per g tissue
Skeletal muscle tissue
Glucose oxidation
c
a
BA
b
CO Donor ( M) CO Donor ( M)
Fig. 3 Effect of CO donor on glucose and fatty acid oxidation in
muscle and white adipose tissue. Data are means ±SEM n=30.
Means with different letters (ac) differed (P\0.05). Tissue
(*100 mg) was incubated at 37"C for 2 h in 1 ml Krebs buffer
containing either 5 mM D-glucose plus D-[U-
14
C]glucose or 0.2 mM
oleic acid plus [1-
14
C]oleic acid. The medium also contained 0, 5, or
30 lM CO donor, [Ru(CO)3Cl2]2. Data are taken from published
work (Li et al. 2009)
354 J. R. McKnight et al.
123
NO, creatine and polyamines, as well as ammonia detoxi-
fication via the urea cycle) or physiological functions (e.g.,
endothelium-dependent relaxation, vascular integrity, and
oxidation of energy substrates) and would potentially
benefit from Arg supplements for weight management. As
noted above, Arg regulates gene expression, mitochondrial
biogenesis, BAT development, and cellular signaling
transduction pathways. Thus, based on the results of animal
studies (Jobgen et al. 2009a; Tan et al. 2009), increasing
Arg provision beyond the need for the maintenance of body
protein may also be beneficial for preventing and treating
obesity in humans who have an average intake of Arg from
diets. As with any other nutrients, improper use of Arg
(e.g., high dose and imbalance among basic amino acids in
Table 2 Concentrations of adenyl purines in insulin-sensitive tissues of lean and obese rats supplemented with or without L-arginine
Tissue Variable LF-Ala LF-Arg HF-Ala HF-Arg Pvalue
Diet AA Diet 9AA
G.
muscle
Arginine 1.31 ±0.10
d
2.09 ±0.14
b
1.67 ±0.12
c
2.65 ±0.16
a
0.01 0.01 0.62
ATP 5.05 ±0.32 5.24 ±0.36 4.95 ±0.29 5.01 ±0.31 0.39 0.24 0.94
ADP 0.68 ±0.05 0.60 ±0.04 0.66 ±0.06 0.63 ±0.05 0.72 0.19 0.85
AMP 0.30 ±0.02
bc
0.27 ±0.01
c
0.37 ±0.02
a
0.32 ±0.02
ab
0.01 0.01 0.41
Adenosine 0.26 ±0.02 0.23 ±0.01 0.24 ±0.02 0.22 ±0.02 0.64 0.42 0.88
cAMP 1.06 ±0.07
b
1.35 ±0.09
a
0.78 ±0.05
c
1.10 ±0.06
b
0.01 0.01 0.53
AMP/
ATP
0.06 ±0.01 0.05 ±0.01 0.07 ±0.01 0.06 ±0.01 0.38 0.18 0.76
WAT Arginine 0.11 ±0.01
d
0.18 ±0.01
b
0.14 ±0.01
c
0.23 ±0.01
a
0.01 0.01 0.25
ATP 0.44 ±0.03 0.46 ±0.05 0.42 ±0.04 0.48 ±0.03 0.58 0.37 0.42
ADP 0.16 ±0.01 0.15 ±0.02 0.14 ±0.02 0.17 ±0.02 0.63 0.82 0.91
AMP 0.08 ±0.01 0.07 ±0.01 0.09 ±0.01 0.10 ±0.02 0.44 0.69 0.83
Adenosine 0.26 ±0.03 0.23 ±0.02 0.24 ±0.02 0.22 ±0.02 0.62 0.14 0.38
cAMP 0.41 ±0.03
a
0.53 ±0.03
a
0.36 ±0.02
b
0.48 ±0.03
b
0.01 0.01 0.55
AMP/
ATP
0.19 ±0.02 0.17 ±0.02 0.21 ±0.02 0.20 ±0.02 0.47 0.59 0.80
BAT Arginine 1.59 ±0.09
d
2.34 ±0.16
b
1.96 ±0.13
c
2.84 ±0.18
a
0.01 0.01 0.27
ATP 3.28 ±0.17 3.41 ±0.22 3.18 ±0.20 3.02 ±0.25 0.76 0.18 0.52
ADP 1.10 ±0.09 1.29 ±0.11 1.22 ±0.10 1.06 ±0.12 0.81 0.90 0.34
AMP 0.48 ±0.03 0.44 ±0.02 0.53 ±0.04 0.50 ±0.03 0.72 0.66 0.49
Adenosine 0.21 ±0.02 0.19 ±0.01 0.20 ±0.02 0.18 ±0.02 0.55 0.47 0.91
cAMP 0.66 ±0.04
b
0.81 ±0.06
a
0.50 ±0.04
c
0.64 ±0.05
b
0.01 0.01 0.20
AMP/
ATP
0.15 ±0.02 0.13 ±0.01 0.17 ±0.02 0.16 ±0.01 0.40 0.86 0.95
Liver Arginine 0.05 ±0.01
b
0.08 ±0.01
a
0.06 ±0.01
b
0.09 ±0.01
a
0.16 0.01 0.74
ATP 4.02 ±0.38 4.28 ±0.30 3.85 ±0.27 3.71 ±0.34 0.72 0.65 0.91
ADP 1.32 ±0.14 1.17 ±0.16 1.05 ±0.12 1.20 ±0.15 0.85 0.72 0.96
AMP 0.42 ±0.04 0.39 ±0.03 0.37 ±0.03 0.41 ±0.05 0.46 0.78 0.50
Adenosine 0.28 ±0.03 0.31 ±0.02 0.26 ±0.02 0.25 ±0.02 0.70 0.59 0.87
cAMP 1.21 ±0.10
b
1.64 ±0.13
a
0.89 ±0.07
c
1.14 ±0.08
b
0.01 0.01 0.46
AMP/
ATP
0.12 ±0.01 0.10 ±0.01 0.10 ±0.01 0.11 ±0.01 0.94 0.81 0.88
Values are mean ±SEM, n=8, and expressed as nmol/g fresh tissue for cAMP and lmol/g fresh tissue for other variables (arginine, ATP,
ADP, AMP, and adenosine). Data were analyzed by two-way analysis of variance and the Tukey multiple comparison test (SAS, Cary, NC,
USA). After a 15-week period of low-fat (LF) or high-fat (HF) feeding, rats continued to receive their respective diets and either 1.51% L-
arginine-HCl (Arg) or 2.55% L-alanine (Ala, isonitrogenous control) in drinking water for 12 weeks (Jobgen et al. 2009a). At the end of the 12-
week period of L-arginine/L-alanine supplementation, various tissues were rapidly obtained and frozen in liquid nitrogen for analysis of adenyl
purines using high performance liquid chromatography (Haynes et al. 2009)
AA amino acid, G. muscle gastrocnemius muscle, WAT white adipose tissue (retroperitoneal adipose tissue), BAT interscapular brown adipose
tissue
a–d
Means in a row with different superscript letters differ (P\0.05)
Arginine and obesity treatment 355
123
the diet) may yield an undesirable effect and should be
avoided in dietary supplementation and clinical therapy
(Baker 2009; Elango et al. 2009; Stipanuk et al. 2009;
Rhoads and Wu 2009). It is advisable that Arg be taken in
divided doses (e.g., up to 3 93 g/day for a 70-kg person)
on each day of supplementation to (1) prevent gastroin-
testinal tract discomfort due to abrupt production of large
amounts of NO; (2) increase the availability of circulating
Arg over a longer period of time; and (3) avoid a potential
imbalance among dietary amino acids (Wu et al. 2009). A
distinct advantage of Arg over drugs (e.g., metformin and
thiazolidinediones) is that dietary Arg supplementation
reduces adiposity while improving insulin sensitivity (Fu
et al. 2005; Jobgen et al. 2009a; Wu et al. 2007b). There-
fore, Arg holds great promise in preventing and treating
obesity in both animals and humans.
Conclusion
Over the past decade, landmark studies have shown that
Arg supplementation is beneficial in reducing adiposity and
improving insulin sensitivity in multiple animal models
and in a limited number of human subjects. The underlying
mechanisms are likely complex at molecular, cellular, and
whole-body levels, but may include the stimulation of
mitochondrial biogenesis and BAT development, as well as
the regulation of gene expression and cellular metabolic
pathways. Arg is expected to play an important role in
fighting the current global obesity epidemic.
Acknowledgments We thank Frances Mutscher and Merrick
Gearing for assistance in manuscript preparation. This work was
supported, in part, by grants from National Institutes of Health (R21
HL094689), National Research Initiative Competitive Grants (2008-
35206-18762, 2008-35206-18764, 2008-35203-19120 and 2009-
35206-05211) from the USDA Cooperative State Research, Educa-
tion, and Extension Service, American Heart Association (0655109Y
and 0755024Y), and Texas AgriLife Research (H-8200).
References
Baker DH (2009) Advances in protein-amino acid nutrition of
poultry. Amino Acids 37:29–41
Bo
¨ger RH, Bode-Bo
¨ger SM (2001) The clinical pharmacology of L-
arginine. Annu Rev Pharmacol Toxiol 41:79–99
Cannon B, Nedergaard J (2004) Brown adipose tissue: function and
physiological significance. Physiol Rev 84:277–359
CDC (2009) Obesity and overweight for professionals: data and
statistics. http://www.cdc.gov/obesity/data/index.html. Accessed
20 Nov 2009
Chung KY, Choi CB, Kawachi H et al (2005) Trans-10, cis-12
conjugated linoleic acid antagonizes arginine-promoted differ-
entiation of bovine preadipocytes. Adipocytes 2:93–100
Cypess AM, Lehman S, Williams G et al (2009) Identification and
importance of brown adipose tissue in adult humans. N Engl J
Med 360:1509–1517
De Luca B, Monda M, Sullo A (1995) Changes in eating behavior and
thermogenic activity following inhibition of nitric oxide forma-
tion. Am J Physiol 268:R1533–R1538
Deng D, Yin YL, Chu WY et al (2009) Impaired translation initiation
activation and reduced protein synthesis in weaned piglets fed a
low-protein diet. J Nutr Biochem 20:544–552
Eklou-Lawson M, Bernard F, Neveux N et al (2009) Colonic luminal
ammonia and portal blood L-glutamine and L-arginine concen-
trations: a possible link between colon mucosa and liver
ureagenesis. Amino Acids 37:751–760
Elango R, Ball RO, Pencharz PB (2009) Amino acid requirements in
humans: with a special emphasis on the metabolic availability of
amino acids. Amino Acids 37:19–27
Flegal KM, Carroll MD, Ogden CL et al (2010) Prevalence and trends
in obesity among US adults, 1999–2008. JAMA 303:235–241
Flynn NE, Bird JG, Guthrie AS (2009) Glucocorticoid regulation of
amino acid and polyamine metabolism in the small intestine.
Amino Acids 37:123–129
Fu WJ, Haynes TE, Kohli R et al (2005) Dietary L-arginine
supplementation reduces fat mass in Zucker diabetic fatty rats.
J Nutr 135:714–721
Garcia-Villafranca J, Guillen A, Castro J (2003) Involvement of nitric
oxide/cyclic GMP signaling pathway in the regulation of fatty acid
metabolism in rat hepatocytes. Biochem Pharmacol 65:807–812
Gaudiot N, Jaubert AM, Charbonnier E et al (1998) Modulation of
white adipose tissue lipolysis by nitric oxide. J Biol Chem
273:13475–13481
Gouill EL, Jimenez M, Binnert C et al (2007) Endothelial nitric oxide
synthase (eNOS) knockout mice have defective mitochondrial
b-oxidation. Diabetes 56:2690–2696
Haas B, Mayer P, Jennissen K et al (2009) Protein kinase G controls
brown fat cell differentiation and mitochondrial biogenesis. Sci
Signal 2(99):ra78
Haynes TE, Li P, Li XL et al (2009) L-Glutamine or L-alanyl-
L-glutamine prevents oxidant- or endotoxin-induced death of
neonatal enterocytes. Amino Acids 37:131–142
He QH, Kong XF, Wu G et al (2009) Metabolomic analysis of the
response of growing pigs to dietary L-arginine supplementation.
Amino Acids 37:199–208
Himmshagen J (1990) Brown adipose tissue thermogenesis: interdis-
ciplinary studies. FASEB J 4:2890–2898
Jobgen WS, Fried SK, Fu WJ et al (2006) Regulatory role for the
arginine-nitric oxide pathway in metabolism of energy sub-
strates. J Nutr Biochem 17:571–588
Jobgen W, Meininger CJ, Jobgen SC et al (2009a) Dietary L-arginine
supplementation reduces white fat gainand enhances skeletal muscle
and brownfat masses in diet-induced obeserats. J Nutr 139:230–237
Jobgen W, Fu WJ, Gao H, Li P et al (2009b) High fat feeding and
dietary L-arginine supplementation differentially regulate gene
expression in rat white adipose tissue. Amino Acids 37:187–198
Kamerman PR, Laburn HP, Mitchell D (2003) Inhibitors of nitric
oxide synthesis block cold-induced thermogenesis in rats. Can J
Physiol Pharmacol 81:834–838
Kersten S (2001) Mechanisms of nutritional and hormonal regulation
of lipogenesis. EMBO Rep 2:282–286
King DE, Mainous AG, Geesey ME (2008) Variation in L-arginine
intake follow demographics and lifestyle factors that may impact
cardiovascular disease risk. Nutr Res 28:21–24
Kohli R, Meininger CJ, Haynes TE et al (2004) Dietary L-arginine
supplementation enhances endothelial nitric oxide synthesis in
streptozotocin-induced diabetic rats. J Nutr 134:600–608
Lehman JJ, Barger PM, Kovacs A et al (2000) Peroxisome
proliferator-activated receptor gamma coactivator 1 promotes
cardiac mitochondrial biogenesis. J Clin Invest 106:847–856
Li X, Bazer FW, Gao H et al (2009) Amino acids and gaseous
signaling. Amino Acids 37:65–78
356 J. R. McKnight et al.
123
Lira VA, Soltow QA, Long JH et al (2007) Nitric oxide increases
GLUT4 expression and regulates AMPK signaling in skeletal
muscle. Am J Physiol Endocrinol Metab 293:E1062–E1068
Lucotti P, Setola E, Monti LD et al (2006) Beneficial effects of a
long-term oral L-arginine added to a hypocaloric diet and
exercise training program in obese, insulin-resistant 2 diabetic
patients. Am J Physiol Endocrinol Metab 291:E906–E912
Ma XY, Lin YC, Jiang ZY et al (2010) Dietary arginine supplemen-
tation enhances antioxidative capacity and improves meat
quality of finishing pigs. Amino Acids 38:95–102
Madsen KL, Brockway PD, Johnson LR et al (1996) Role of ornithine
decarboxylase in enterocyte mitochondrial function and integ-
rity. Am J Physiol 270:G789–G797
McConell GK, Ng GP, Phillips M et al (2009) Central role of nitric oxide
synthase in AICAR and caffeine induced mitochondrial biogenesis
in L6 myocytes. J Appl Physiol. doi:10.1152/japplphysiol.00377.
2009
Mendez JD, Balderas F (2001) Regulation of hyperglycemia and
dyslipidemia by exogenous L-arginine in diabetic rats. Biochimie
83:453–458
Mersmann HJ, Smith SB (2005) Development of white adipose tissue
lipid metabolism. In: Burrin DG, Mersmann HJ (eds) Biology of
metabolism in growing animals. Elsevier, Oxford, pp 275–302
Nisoli E, Carruba MO (2004) Emerging aspects of pharmacotherapy
for obesity and metabolic syndrome. Pharmacol Res 50:453–469
Nisoli E, Clementi E, Paolucci C et al (2003) Mitochondrial
biogenesis in mammals: the role of endogenous nitric oxide.
Science 299:896–899
Nisoli E, Falcone S, Tonello C et al (2004) Mitochondrial biogenesis
by NO yields functionally active mitochondria in mammals. Proc
Natl Acad Sci USA 101:16507–16512
Nisoli E, Cozzi V, Carruba MO (2008) Amino acids and mitochon-
drial biogenesis. Am J Cardiol 101S:22E–25E
Palii SS, Kays CE, Deval C et al (2009) Specificity of amino acid
regulated gene expression: analysis of gene subjected to either
complete or single amino acid deprivation. Amino Acids 37:79–88
Petrovic V, Buzadzic B, Korac A et al (2008) Antioxidative defence
alterations in skeletal muscle during prolonged acclimation to
cold: role of L-arginine/NO-producing pathway. J Exp Biol
211:114–120
Petrovic
´V, Korac
´A, Buzadzic
´B et al (2005) The effects of
L-arginine and L-NAME supplementation on redox-regulation
and thermogenesis in interscapular brown adipose tissue. J Exp
Biol 208:4263–4271
Petrovic
´V, Korac
´A, Buzadzic
´B et al (2008) Nitric oxide regulates
mitochondrial re-modelling in interscapular brown adipose
tissue: ultrastructural and morphometric-stereologic studies.
J Microsc 232:542–548
Petrovic
´V, Buzadz
ˇic
´B, Korac
´A et al (2010) Antioxidative defense
and mitochondrial thermogenic response in brown adipose
tissue. Genes Nutr. doi:10.1007/s12263-009-0162-1
Phang JM, Donald SP, Pandhare J et al (2008) The metabolism of
proline, as a stress substrate, modulates carcinogenic pathways.
Amino Acids 35:681–690
Pi-Sunyer X (2003) A clinical view of the obesity problem. Science
299:859–860
Power GG (1989) Biology of temperature: the mammalian fetus.
J Dev Physiol 12:295–304
Puigserver P, Wu ZD, Park CW et al (1998) A cold-inducible
coactivator of nuclear receptors linked to adaptive thermogen-
esis. Cell 92:829–839
Rhoads JM, Wu G (2009) Glutamine, arginine, and leucine signaling
in the intestine. Amino Acids 37:111–122
Saha SK, Ohinata H, Kuroshima A (1996) Effects of acute and
chronic inhibition of nitric oxide synthase on brown adipose
tissue thermogenesis. Jpn J Physiol 46:375–382
Satterfield MC, Bazer FW, Smith SB et al (2009) Arginine nutrition
and fetal brown fat development. Amino Acids 37(Suppl. 1):6–7
Scammell TE, Elmquist JK, Saper CB (1996) Inhibition of nitric
oxide synthase produces hypothermia and depresses lipopoly-
saccharide fever. Am J Physiol 271:R333–R338
Stipanuk MH, Ueki I, Dominy JE et al (2009) Cysteine dioxygenase:
a robust system for regulation of cellular cysteine levels. Amino
Acids 37:55–63
Suryawan A, O’Connor PMJ, Bush JA et al (2009) Differential
regulation of protein synthesis by amino acids and insulin in
peripheral and visceral tissues of neonatal pigs. Amino Acids
37:97–104
Tan BE, Yin YL, Liu ZQ et al (2009) Dietary L-arginine supplemen-
tation increases muscle gain and reduces body fat mass in
growing-finishing pigs. Amino Acids 37:169–175
Tan B, Yin Y, Kong X et al (2010) L-Arginine stimulates proliferation
and prevents endotoxin-induced death of intestinal cells. Amino
Acids. doi:10.1007/s00726-009-0334-8
van Marken Lichtenbelt WD, Vanhommerig JW et al (2009) Cold-
activated brown adipose tissue in healthy men. N Engl J Med
360:1500–1508
Virtanen KA, Lidell ME, Orava J et al (2009) Functional brown
adipose tissue in healthy adults. N Engl J Med 360:1518–1525
Wadley GD, McConell GK (2007) Effect of nitric oxide synthase
inhibition on mitochondrial biogenesis in rat skeletal muscle.
J Appl Physiol 102:314–320
Wang XQ, Ou DY, Yin JD et al (2009a) Proteomic analysis reveals
altered expression of proteins related to glutathione metabolism
and apoptosis in the small intestine of zinc oxide-supplemented
piglets. Amino Acids 37:209–218
Wang WW, Qiao SY, Li DF (2009b) Amino acids and gut function.
Amino Acids 37:105–110
Wang JJ, Wu G, Zhou HJ et al (2009c) Emerging technologies for
amino acid nutrition research in the post-genome era. Amino
Acids 37:86–177
World Health Organization (WHO) (2009) World health statistics-
2009. http://www.who.int. Accessed 2 Mar 2010
Wu G (2009) Amino acids: metabolism, functions, and nutrition.
Amino Acids 37:1–17
Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular
function. J Nutr 130:2626–2629
Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and
beyond. Biochem J 336:1–17
Wu ZD, Puigserver P, Anderson U et al (1999) Mechanisms
controlling mitochondrial biogenesis and respiration through
the thermogenic coactivator PGC-1. Cell 98:115–124
Wu G, Bazer FW, Cudd TA et al (2007a) Pharmacokinetics and safety
of arginine supplementation in animals. J Nutr 137:1673S–1680S
Wu G, Collins JK, Perkins-Veazie P et al (2007b) Dietary supple-
mentation with watermelon pomace juice enhances arginine
availability and ameliorates the metabolic syndrome in Zucker
diabetic fatty rats. J Nutr 137:2680–2685
Wu G, Bazer FW, Davis TA et al (2009) Arginine metabolism and
nutrition in growth, health and disease. Amino Acids 37:153–
168
Yao K, Yin YL, Chu W et al (2008) Dietary arginine supplementation
increases mTOR signaling activity in skeletal muscle of neonatal
pigs. J Nutr 138:867–872
Yin FG, Liu YL, Yin YL et al (2009) Dietary supplementation with
astragalus polysaccharide enhances ileal digestibilities and
serum concentrations of amino acids in early weaned piglets.
Amino Acids 37:263–270
Yongyi B, Sun L, Yang T et al (2009) Increase in fasting vascular
endothelial function after short-term oral L-arginine is effective
when baseline flow-mediated dilation is low: a mega-analysis of
randomized controlled trials. Am J Clin Nutr 89:77–84
Arginine and obesity treatment 357
123
... Along with the present study, in most studies with or without supplementation in which long-term aerobic exercise protocols were used, the changes in physical characteristics of the subjects were tangible (12,34). For example, Prado et al showed that following an intervention of 12 weeks of high and low intensity training in 36 adolescent boys and girls, the physical features such as weight, BMI and PBF after the protocol significantly reduced compared to pre-protocol conditions so that this decrease was more significant in the HIT group (12). ...
... The participants were randomly divided into two HIT + arginine and HIT + placebo groups, the body indices such as weight, BMI, and PBF significantly improved with the completion of the research compared with baseline values. It should be noted that these changes in the arginine group were greater than the placebo group (34). The factors contributing to the supplemental role of L-arginine as a factor in reducing obesity are probably a complex mechanism at cellular-molecular levels and the whole body so that the mitochondrial biogenesis stimulation and regulating gene expression and metabolic pathways via L-arginine are expected. ...
... The factors contributing to the supplemental role of L-arginine as a factor in reducing obesity are probably a complex mechanism at cellular-molecular levels and the whole body so that the mitochondrial biogenesis stimulation and regulating gene expression and metabolic pathways via L-arginine are expected. Therefore, the use of L-arginine supplementation for obese people induces fat loss and prevents the reduction of body mass during weight loss (34). ...
Article
Background: There is little information about the effects of high intensity aerobic exercise training (HIT) and L-arginine supplementation on appetite-regulating hormones among obese male adolescents. We aimed to determine the effect of eight weeks of HIT and L-arginine supplementation on appetite-regulating hormones and body composition indices in obese adolescent boys. Methods: Twenty obese adolescents were randomly divided into two groups of HIT and placebo (P-HIT, n=10) and HIT with supplementation of L-arginine (A-HIT, n=10). The HIT protocol was treadmill running with ventilation threshold (VT) intensity and training sessions were isoenergetic and energy consumption were set to 350 kcal per session for each participant, which were evaluated indirectly by calorimetry. The A-HIT group received 3 g of L-arginine per day for 8 weeks. Before the interventions and 48 hours after the last exercise session, anthropometric indices and levels of appetite-regulating hormones were measured. Results: There was no significant changes between the groups with respect to leptin, agouti, and PYY3-36 peptide levels. There were significant changes in weight reduction between the groups (P≤0.05). However, body max index (BMI) and percent body fat (PBF) changes were not significant in between groups (P≥0.05). Conclusion: Our findings suggest that co-supplementation of L-arginine with HIT training had no further effects on appetite regulatory hormones and body composition of obese male adolescents.
... Further, we found that the beneficial effect of Arg on metabolic health was mediated partially through the activation of hepatic AMP-activated protein kinase (AMPK) (Jobgen 2007;Jobgen and Wu 2022). However, the underlying biochemical mechanisms remain largely unknown (McKnight et al. 2010;Mariotti 2020;Szlas et al. 2022). ...
... As a stimulator of mitochondrial biogenesis, a vasodilator, and cell signaling molecule, NO has been suggested to modulate energy metabolism, fat deposition in white adipocytes, and insulin resistance in mammals including humans (Sansbury and Hill 2014) and rats (McKnight et al. 2010;Peyton et al. 2018;Wu 2022). Interestingly, increasing extracellular concentrations of Arg from 0 to 400 μM increased NO synthesis in BNL CL.2 cells, as reported for Arg-treated rat hepatocytes (Morita et al. 1996). ...
Article
Full-text available
Previous work has shown that dietary l-arginine (Arg) supplementation reduced white fat mass in obese rats. The present study was conducted with cell models to define direct effects of Arg on energy-substrate oxidation in hepatocytes, skeletal muscle cells, and adipocytes. BNL CL.2 mouse hepatocytes, C2C12 mouse myotubes, and 3T3-L1 mouse adipocytes were treated with different extracellular concentrations of Arg (0, 15, 50, 100 and 400 µM) or 400 µM Arg + 0.5 mM NG-nitro-l-arginine methyl ester (L-NAME; an NOS inhibitor) for 48 h. Increasing Arg concentrations in culture medium dose-dependently enhanced (P < 0.05) the oxidation of glucose and oleic acid to CO2 in all three cell types, lactate release from C2C12 cells, and the incorporation of oleic acid into esterified lipids in BNL CL.2 and 3T3-L1 cells. Arg at 400 µM also stimulated (P < 0.05) the phosphorylation of AMP-activated protein kinase (AMPK) in all three cell types and increased (P < 0.05) NO production in C2C12 and BNL CL.2 cells. The inhibition of NOS by L-NAME moderately reduced (P < 0.05) glucose and oleic acid oxidation, lactate release, and the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in BNL CL.2 cells, but had no effect (P > 0.05) on these variables in C2C12 or 3T3-L1 cells. Collectively, these results indicate that Arg increased AMPK activity and energy-substrate oxidation in BNL CL.2, C2C12, and 3T3-L1 cells through both NO-dependent and NO-independent mechanisms.
... L-arginine supplementation has been demonstrated to be beneficial for endotheliumderived NO production and endothelial function in numerous studies, reducing systemic blood pressure in some forms of experimental hypertension (10). Animal studies have shown that arginine reduces white fat mass while increasing brown fat and skeletal muscle mass, increases several lipolytic enzymes, and reduces the levels of insulin resistance (IR) (11)(12)(13)(14). Moreover, L-arginine concentrations in the intracellular environment have a direct impact on the metabolic fitness and survival capacities of T cells which are crucial for anti-tumor immunity (15). ...
Article
Full-text available
Objective The effect of arginine on tumors appears to be bidirectional. The association of serum arginine with the risk of incident cancer remains uncovered at present. We aimed to investigate the prospective relationship of baseline serum arginine concentrations with the risk of incident cancer in hypertensive participants. Materials and methods A nested, case-control study with 1,389 incident cancer cases and 1,389 matched controls was conducted using data from the China H-Type Hypertension Registry Study (CHHRS). Conditional logistic regression analyses were performed to evaluate the association between serum arginine and the risk of the overall, digestive system, non-digestive system, and site-specific cancer. Results Compared with matched controls, cancer patients had higher levels of arginine (21.41 μg/mL vs. 20.88 μg/mL, p < 0.05). When serum arginine concentrations were assessed as quartiles, compared with participants in the lowest arginine quartile, participants in the highest arginine quartile had a 32% (OR = 1.32, 95% CI: 1.03 to 1.71), and 68% (OR = 1.68, 95% CI: 1.09 to 2.59) increased risk of overall and digestive system cancer, respectively, in the adjusted models. In the site-specific analysis, each standard deviation (SD) increment of serum arginine was independently and positively associated with the risk of colorectal cancer (OR = 1.35, 95% CI: 1.01 to 1.82) in the adjusted analysis. Conclusion We found that hypertensive individuals with higher serum arginine levels exhibited a higher risk of overall, digestive system, and colorectal cancer.
... 58 The nutritional and therapeutic roles of L-arginine are known in treating and preventing human metabolic disorders, including managing weight gain and reducing obesity. McKnight et al 59 reported that L-arginine reduced adiposity by stimulating mitochondrial biogenesis and brown adipose tissue development through enhanced synthesis of cell signalling molecules (polyamines, nitric oxide, carbon monoxide, cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP)), as well as increasing the expression of genes that promote whole-body oxidation of energy substrates (glucose and fatty acids). ...
Article
Full-text available
Honey has a long history of therapeutic properties for multiple diseases, including inflammation and oxidative stress. This review aimed to provide a better understanding and renewed interest in the potential role of honey in obesity control, obesity-related diseases treatment and weight management, with specific reference to its components and the effect of honey overall. There is compelling evidence that honey possesses the desired properties for this purpose, as seen in the in vitro, in silico, in vivo and clinical analyses discussed in this review. This review also highlights the components potentially responsible for the health benefits of honey. Honey and its components reduce blood sugar levels, improve insulin sensitivity and lipid metabolism by reducing triglycerides, and reduce total cholesterol and LDL levels while increasing HDL levels that prevent excessive weight gain and reduce the risk of obesity and its complications. Further controlled studies are necessary to validate the role of honey in the management of obesity, both as a preventive and as a therapeutic agent.
... In addition, arginine can be used for effective therapy for obesity, diabetes, and metabolic syndrome. [27][28][29] Leucine is an essential amino acid that is often used as a supplement or additive for the purpose of nutrification or enrichment in dietary foods. 30,31 This causes leucine to be used for the treatment of obesity as well as metabolic syndrome. ...
Article
Full-text available
One of the interesting marine products to be explored is flying fish (Hirundichthys oxycephalus) roes. The flying fish roe is usually called tobiko. The aim of this study is to extract protein from tobiko filaments using an isoelectric point approach, analyze their chemical properties, and apply them to the nutrification of rice-corn milk. Extraction of tobiko filaments using an isoelectric point approach resulted in an optimal pH of 8.5 based on the protein content (73.52 ± 0.07 %). Extraction under alkaline conditions (pH 8.5) resulted in a protein concentrate yield of 9.04% and an insoluble portion of 69.79%. That protein concentrate showed 15 amino acid, leucin (5.86 ± 0.01%), lycin (3.69 ± 0.02%), valin (3.41 ± 0.02%), isoleucine (3.33 ± 0.01%), threonine (2.86 ± 0.01%), phenylalanine (2.30 ± 0.02%), histidine (1.38 ± 0.01%), and methionine (1.21 ± 0.01%), glutamate (7.08 ± 0.01%), arginine (6.11 ± 0.01%), alanine (3.82 ± 0.01%), aspartic acid (3.75 ± 0.01%), serine (3.05 ± 0.02%), glycine (1.84 ± 0.01%), and tyrosine (1.46 ± 0.01%). The addition of protein concentrate from tobiko filament showed an increase in protein content in rice-corn milk so the purpose of nutrification in this study was successful. The best formulation is in the composition of rice: corn: protein concentrate (15:5:3%) with details of moisture content 65.07 ± 0.02%, ash content 0.50 ± 0.01%, the lipid content 0.28 ± 0.02%, the protein content 21.18 ± 0.02 %, the carbohydrate content 12.95 ± 0.02%, with a total energy 278.13 ± 0.03 kcal.
... Of particular note, a systematic review and meta-analysis of 12 randomized clinical trials involving a total of 736 obese persons reveals that the oral administration of 3 to 9 g Arg/day for up to 77 weeks reduced body mass index, waist circumference, and white-fat mass, while enhancing fat-free lean mass, when compared to the placebo group (Khosroshahi et al. 2020). To date, the molecular mechanisms responsible for the anti-obesity effect of Arg supplementation remain largely unknown (McKnight et al. 2010;Mariotti 2020;Szlas et al. 2022). The present study was conducted to test the hypothesis that dietary Arg supplementation regulates the expression of AMPK, ACC, and PGC-1α, and possibly other key enzymes involved in the metabolism of energy substrates in insulin-sensitive tissues. ...
Article
Full-text available
The goal of this study was to elucidate the molecular mechanisms responsible for the anti-obesity effect of L-arginine supplementation in diet-induced obese rats. Male Sprague–Dawley rats were fed either a low-fat or high-fat diet for 15 weeks. Thereafter, lean or obese rats were pair-fed their same respective diets and received drinking water containing either 1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) for 12 weeks. Gene and protein expression of key enzymes in the metabolism of energy substrates were determined using real-time polymerase-chain reaction and western blotting techniques. The mRNA levels of hepatic fatty acid synthase and stearoyl-CoA desaturase were reduced (P < 0.05) but those of hepatic AMP-activated protein kinase-α (AMPKα), peroxisome proliferator activator receptor γ coactivator-1α, and carnitine palmitoyltransferase I (CPT-I), as well as skeletal muscle CPT-I were increased (P < 0.05) by L-arginine treatment. The protein expression and activity of hepatic AMPKα markedly increased (P < 0.05) but the activity of hepatic acetyl-CoA carboxylase (ACC) decreased (P < 0.05) in response to dietary L-arginine supplementation. Collectively, our results indicate that liver is the major target for the action of dietary L-arginine supplementation on reducing white-fat mass in diet-induced obese rats by inhibiting fatty acid synthesis and increasing fatty acid oxidation via the AMPK-ACC signaling pathway. Additionally, increased CPT-I expression in skeletal muscle may also contribute to the enhanced oxidation of long-chain fatty acids in L-arginine-supplemented rats.
... Arginine, one of the conditionally essential AA, has been reported to stimulate body fat metabolism and milk fat production in nonruminant mammals, McKnight et al., 2010). For example, a recent study in sows found that dietary supplementation with Arg increased the milk fat percentage and daily milk fat yield without affecting daily DMI (Moreira et al., 2018). ...
Article
Full-text available
Arginine, one of the conditionally essential AA, has been reported to affect fat synthesis and metabolism in nonruminant animals by influencing adenosine monophosphate activated protein kinase (AMPK) in some organs. In dairy cows, the effect of Arg on milk fat production is not clear, and any potential mechanism that underlies the effect is unknown. We tested the hypothesis that Arg infusion would improve the production of milk fat, and explored possible mechanism that might underlie any effect. We used 6 healthy lactating cows at 20 ± 2 d in milk, in fourth parity, with a body weight of 508 ± 14 kg, body condition score of 3.0 ± 0, and a milk yield of 30.6 ± 1.8 kg/d (mean ± standard deviation). The cows were blocked by days in milk and milk yield and each cow received 3 treatments in a replicated 3 × 3 Latin square design, with each of the experimental periods lasting 7 d with a 14-d washout between each period. The treatments, delivered in random order, were (1) infusion of saline (control); (2) infusion of 0.216 mol/d of l-Arg in saline (Arg); (3) infusion of 0.868 mol/d of l-Ala in saline (the Arg and Ala treatments were iso-nitrogenous) through a jugular vein. On the last day of each experimental period, blood was sampled to measure insulin, nitric oxide, glucose, and nonesterified fatty acid, and the liver and mammary gland were biopsied to measure the expression of genes. Milk yield was recorded, and milk fat percentage was measured daily during each of the experimental periods. The yield and composition of fatty acid (FA) in milk was measured daily on the last 3 d during each of the experimental periods. The data were analyzed using a mixed model with treatment as a fixed factor, and cow, period, and block as random factors. The daily milk yield and milk fat yield when the cows were infused with Arg were 2.2 kg and 76 g, respectively, higher than that in control, and 1.8 kg and 111 g, respectively, higher than that in Ala. When the cows were infused with Arg they had higher concentration and yield of de novo synthesized FA, than when they received the control or Ala infusions, although milk fat percentage, daily feed intake, and the digestibility of nutrients were not affected by treatment. The serum concentration of nitric oxide and insulin were higher during Arg than during control or Ala, with no difference between control and Ala. In the liver, the expression of the genes coding for AMPK (PRKAA1, PRKAB1, and PRKAG1) and genes related to the oxidation of FA were higher during Arg than during control or Ala, whereas in the mammary gland the expression PRKAB1 was lowest, and the expression of genes involved in the synthesis of milk fat were highest, during Arg infusion. The results suggest the intravenous infusion of Arg enhanced the production of milk fat by promoting the de novo synthesis of FA and increasing milk yield.
... [26] Improving cardiovascular function and enhancing lean tissue mass, arginine is widely used as dietary supplement also to reduce obesity. [27] In plants, arginine, the AA with the highest N:C ratio amid the 21 proteinogenic amino acids, serves to store nitrogen as well as in defending plants against different stress agents. [28] Called "a metabolic hub" [29] and formed only in glial cells, serine links glial metabolism with synaptic activity and plasticity to such an extent that its lack contributes to many brain disorders. ...
Preprint
Full-text available
The analysis via GC-MS of the amino acids present in AnchoisFert, a new organic fertilizer co-product of fish oil extraction from anchovy fillet leftovers using limonene, unveils the presence of 16 amino acids, essential, quasi-essential and non-essential. Leucine, glycine, glutamic acid and alanine are the most abundant AAs. Proline, aspartic acid, arginine, serine, lysine and phenylalanine are also relatively plentiful. Alongside the results of the techno-economic and life cycle assessment analyses, these outcomes suggest that the “LimoFish” circular economy process is highly effective in recovering valued AAs that otherwise would be lost in the environment. This greatly improves the sustainability of anchovy fishing, processing and consumption, further supporting the scale-up and industrialization of the process.
... Hitherto, the effect of L-arginine on body fat reduction has been mainly ascribed to increased lipolysis in response to L-arginine-induced increase in energy metabolism in muscles and BAT [13,18,23,47]. In agreement, hydrolysis of triacylglycerols (as indicated by increased protein expression of HSL and ATGL) in rpWAT by L-arginine treatment may increase consequently to meet the energy requirements of BAT [9,48] and skeletal muscles [39,49], as shown in our previous studies. ...
Article
Full-text available
The beneficial effects of l-arginine supplementation in obesity and type II diabetes involve white adipose tissue (WAT) reduction and increased substrate oxidation. We aimed to test the potential of l-arginine to induce WAT browning. Therefore, the molecular basis of browning was investigated in retroperitoneal WAT (rpWAT) of rats exposed to cold or treated with 2.25% l-arginine for 1, 3, and 7 days. Compared to untreated control, levels of inducible nitric oxide (NO) synthase protein expression and NO signaling increased in both cold-exposed and l-arginine-treated groups. These increases coincided with the appearance of multilocular adipocytes and increased expression levels of uncoupling protein 1 (UCP1), thermogenic and beige adipocyte-specific genes (Cidea, Cd137, and Tmem26), mitochondriogenesis markers (peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α, mitochondrial DNA copy number), nuclear respiratory factor 1, PPARα and their respective downstream lipid oxidation enzymes after l-arginine treatment. Such browning phenotype in the l-arginine-treated group was concordant with end-course decreases in leptinaemia, rpWAT mass, and body weight. In conclusion, l-arginine mimics cold-mediated increases in NO signaling in rpWAT and induces molecular and structural fingerprints of rpWAT browning. The results endorse l-arginine as a pharmaceutical alternative to cold exposure, which could be of great interest in obesity and associated metabolic diseases.
... As shown on our results, the supplementation with L-arginine decreased the plasma concentration of triglycerides at 60 days of gestation, without significant impact on another periods of the study. This reduction occurs because arginine, among its various functions, promotes the formation of ornithine, ammonia detoxification and muscle protein synthesis (which is fundamental for the development of fetuses), while at the same time, it stimulates the oxidation of fatty acids and inhibits the synthesis of long-chain fatty acids, as well as triglycerides, reducing their circulating rate in plasma (McKnight et al., 2010;Wu et al., 2012). These results are in agreement with those of Hu et al. (2015), who evaluated the use of long term dietary supplementation with L-arginine-HCl or L-arginine, for pigs from 30 days of age to 121 days of age, found that the dietary supplementation from 0.5 to 2% of arginine decreased plasma concentrations of triglyceride, free fatty acids, and cholesterol, besides glutamine, glycine, and ammonia. ...
Article
The high prolificacy achieved by the genetic improvement of sows has resulted in decreased birth weights and uniformity of litters, as well as increased prenatal and preweaning mortality. Amino acids, such as arginine, are essential for the proper development of the placenta and the swine fetus. Their role include regulating angiogenesis, vascular development, and therefore potentially placental vascularization, providing a greater supply of nutrients and oxygen from the sow to the fetuses. The objective of the trial was to evaluate the effects of dietary l-arginine supplementation on the reproductive and productive performance of gestating sows from days 30 to 60 and days 80 to 114 of gestation. Forty-eight pluriparous sows with two to six parities were divided into two different treatments with a total of 24 replicates per treatment. The treatments consisted of a control diet without l-arginine supplementation (CON) and a diet with top-dressed supplementation of 1.0% l-arginine (ARG). Blood samples were collected from the sows on days 30, 60, 90, and 114 of gestation to determine the plasma concentrations of albumin, creatinine, and urea. Sows were weighed 24 h after farrowing and at weaning to calculate body weight loss during lactation. Piglets were individually weighed at birth before the first feeding and at weaning. Supplementation of the diet with l-arginine during gestation affected (p = 0.025) the plasma concentrations of triglycerides at 60 days, but it did not impact the albumin, creatinine, and urea's concentrations at 30, 60, 90, and 114 days of gestation. However, the concentrations of creatinine differed (p = 0.006) for gestational periods. The average weight of piglets born alive was greater (p = 0.0485) for ARG compared to CON and the other performance and reproductive characteristics did not differ. The percentage of piglets born weighing over 1.81 kg was greater (p < 0.05) for sows fed ARG than in CON fed sows. l-arginine supplementation in the feed of gestating sows increased the average weight of piglets born alive and the percentage of piglets with a birth weight above 1.81 kg, reduced the concentration of triglycerides at 60 days of gestation, and the gestational period had effect about the creatinine concentrations.
Article
Full-text available
The trans-10, cis-12 isomer of CLA (t10, c12 CLA), synthesized by ruminal microflora, has been reported to be a potent inhibitor of preadipocyte differentiation in rodents. Conversely, arginine promotes the differentiation of 3T3-L1 preadipocytes. We hypothesized that arginine would promote differentiation by up-regulating expression of PPARγ, in bovine primary preadipocytes in culture, and that this effect would be antagonized by t10, c12 CLA. The objectives of this study were to establish conditions for the culture of preadipocytes from bovine adipose tissue and to document interaction between arginine and isomers of CLA on differentiation. Bovine stromal-vascular (SV) cells were collagenase-liberated from perirenal adipose tissue of 16-mo-old, corn-fed Angus steers. Extracted RNA from the cells was hybridized to antisense RNA probes. The expression of stearoyl-CoA desaturase (SCD) and fatty acid synthase (FAS) was undetectable in preconfluent preadipocytes, but increased strongly after 7 d of treatment with 10μg/mL insulin, 10μg/ mL holo-transferrin, and 5μM pioglitazone, especially in the absence of dexamethasone. The t10, c12 CLA isomer decreased SCD and FAS gene expression in a dose-dependent fashion when added during the last 3 d of differentiation; the cis-9, trans-11 CLA isomer was without effect except at the highest concentration tested (100 μM). Similarly, t10, c12 CLA (but not c9, t11 CLA) depressed the monounsaturated fatty acid: saturated fatty acid ratio in differentiating preadipocytes and depressed acetate incorporation into fatty acids. PPARγ, SCD, lipoprotein lipase, TNFα and Pref-1, but not C/EBPβ, exhibited greater expression in preadipocytes treated with 5 mM arginine during differentiation than in control preadipocytes. The t10, c12 CLA isomer (at 40 μM) strongly decreased SCD and PPARγ expression, even in the presence of 5 mM arginine. We conclude that arginine can up-regulate differentiation of bovine preadipocytes, and t10, c12 CLA strongly antagonizes this effect.
Article
Full-text available
Early in cold acclimation (1–7 days), heat is produced by shivering,while late in cold acclimation (12–45 days), skeletal muscle contributes to thermogenesis by tissue metabolism other than contractions. Given that both thermogenic phases augment skeletal muscle aerobic power and reactive species production, we aimed in this study to examine possible changes in skeletal muscle antioxidative defence (AD) during early and late cold acclimation with special emphasis on the influence of the l-arginine/nitric oxide(NO)-producing pathway on the modulation of AD in this tissue. Adult Mill Hill hybrid hooded rat males were divided into two main groups: a control group,which was kept at room temperature (22±1°C), and a group maintained at 4±1°C for 45 days. The cold-acclimated group was divided into three subgroups: untreated, l-arginine treated and Nω-nitro-l-arginine methyl ester(l-NAME) treated. The AD parameters were determined in the gastrocnemius muscle on day 1, 3, 7, 12, 21 and 45 of cold acclimation. The results showed an improvement of skeletal muscle AD in both early and late cold acclimation. Clear phase-dependent changes were seen only in copper, zinc superoxide dismutase activity, which was increased in early cold acclimation but returned to the control level in late acclimation. In contrast, there were no phase-dependent changes in manganese superoxide dismutase, catalase,glutathione peroxidase, glutathione reductase and glutathione S-transferase,the activities of which were increased during the whole cold exposure,indicating their engagement in both thermogenic phases. l-Arginine in early cold acclimation accelerated the cold-induced AD response, while in the late phase it sustained increases achieved in the early period. l-NAME affected both early and late acclimation through attenuation and a decrease in the AD response. These data strongly suggest the involvement of the l-arginine/NO pathway in the modulation of skeletal muscle AD.
Article
Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% [76/1013]) than in men (3.1% [30/959]); the female:male ratio was 2.4:1.0 (P 64) (P 64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.
Article
Changes in inducible nitric oxide synthase (iNOS) protein levels and its relationship with the hyperplasia and uncoupling protein 1 (UCP1) levels were examined in interscapular brown adipose tissue (IBAT) of adult rat males receiving L-arginine (L-Arg; 2.25%) or N-nitro-L-arginine methyl ester (L-NAME; 0.01 %) as a drinking liquid and maintained-at low (4 +/- 1 degrees C) or room (22 +/- 1 degrees C) temperature for 45 days. Cold generally diminished both iNOS immunopositivity and protein level in IBAT, as well as the rate of apoptosis. Among groups acclimated to cold, higher iNOS immunopositivity and protein levels were detected only in the L-Arg-treated group. Furthermore, chronic L-Arg treatment increased IBAT mass and UCP1 protein content, while L-NAME had an opposite effect, decreasing both IBAT mass and UCP1 protein level, as compared to the control maintained at 4 1 degrees C. These data suggest that nitric oxide (NO) produced by iNOS could also contribute to overall NO-associated regulation of thermogenesis in IBAT. Namely, that MOS, i.e. NO, in correlation with enhanced thermogenesis, additionally induced MAT hyperplasia and UCP1 level compared to that induced by low temperature. Cooperative action of decreased apoptosis accompanied by increased tissue hyperplasia and UCP1 level, observed in IBAT of cold-acclimated rats, would be a way of meeting the metabolic requirements for increased thermogenesis.
Article
Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.