ASN 2012 ANNUAL MEETING SYMPOSIUM SUMMARIES
The Role of Dietary Components
in Leptin Resistance1,2
Joseph R. Vasselli*
Obesity Research Center, Department of Medicine, St. Luke’s-Roosevelt Hospital, and Columbia University Institute of Human Nutrition,
New York, NY
Introduction
Leptin resistance has been defined as reduced or absent
responsiveness to the feeding and body weight inhibitory
effects of the hormone in obese individuals compared
with normal (lean) controls. Classically, leptin resistance
has been associated with increased body fat and circulating
leptin levels, and the effect is thought to contribute to the
maintenance of obesity. Whereas a great deal is known
about the central nervous system (CNS)3 mechanisms asso-
ciated with leptin resistance, considerably less is known
about the role of diet in establishing and maintaining this
altered hormonal state. Recently, new data have emerged in-
dicating that specific types of dietary sugars or fats are capa-
ble of inducing leptin resistance in the absence of elevated
levels of circulating leptin and/or body fat. These findings
suggest that specific macronutrients may be involved in
the induction of leptin resistance prior to the development
of obesity, and open the possibility that diet-induced leptin
resistance may play a role in the onset of weight gain leading
to obesity. This review will present new findings by 4 inves-
tigators on the role of diet in leptin resistance, including the
effects of type and form of dietary sugar, the effect of dietary
TG saturation, and potential metabolic and CNS mecha-
nisms mediating these effects. These data were presented
at a symposium sponsored by the ASN and held at the Ex-
perimental Biology 2012 Meeting, San Diego, CA on April
22, 2012.
1
This article is a summary of the symposium “The Role of Dietary Components in Leptin
Resistance” held April 22, 2012 at the ASN Scientific Sessions and Annual Meeting at
Experimental Biology 2012 in San Diego, CA. The symposium was sponsored by the ASN
and supported in part by educational grants from Research Diets, Inc, PepsiCo, and Pharma
Science Nutrients, Inc. The symposium organizer has indicated that related reviews from
this symposium will be submitted for publication in an upcoming issue of Advances in
Nutrition.
2
Author disclosure: J. R. Vasselli, no conflicts of interest.
3
Abbreviations used: BBB, blood brain barrier; CNS, central nervous system; HBP, hexosamine
biosynthetic pathway; HFD, high-fat diet; PSTAT3, phosphorylated signal transducer and
activator of transcription 3; O-linked, O-glycan linked; STAT3, signal transducer and activator
of transcription 3.
* To whom correspondence should be addressed. E-mail: jrv1@columbia.edu.
736
The role of fructose and overnutrition in
leptin resistance
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Our first topic was presented by Philip J. Scarpace, Univer-
sity of Florida, Gainesville, FL. Sucrose, a natural sweetener,
imparts palatability to food and contributes to the con-
sumption of excess energy. Fructose, one component of su-
crose, has been implicated in the obesity epidemic. We
addressed whether there is a specific role for fructose, be-
yond its energetic impact, in promoting obesity. We exam-
ined the effects in rats of isoenergetic, low-fat diets with
increasing concentrations of fructose on hyperphagia and
weight gain. Compared with a fructose-free diet, fructose
contents of 20 or 40% induced hyperphagia and weight
gain, whereas a 60% fructose diet did not. The observation
that the 60% fructose diet did not result in palatability-
driven hyperphagia allowed us to examine whether dietary
fructose contributes to obesity through a mechanism inde-
pendent of hyperphagia. We examined leptin responsiveness
after 6 mo of feeding a 60% fructose diet and found the fruc-
tose-fed rats were resistant to the feeding-inhibitory effects
of peripheral leptin. More importantly, this leptin resistance
exacerbated weight gain in response to a subsequent high-fat
challenge. When fructose was formulated with a high-fat
diet (HFD), there was greater weight gain and the presence
of leptin resistance compared with a matched HFD without
sugar. Moreover, removal of the fructose reversed the leptin
resistance and halted the excessive weight gain. An examina-
tion of central leptin signaling revealed that the high-fat,
sugar-containing diet associated with hyperphagia resulted
in impaired signal transducer and activator of transcription
3 (STAT3) phosphorylation, whereas the high-fructose diet
in the absence of obesity resulted in an impaired leptin-
mediated decrease in AMPK phosphorylation. In summary,
dietary fructose contributes to obesity through 2 mechanisms;
palatability-driven hyperphagia and weight gain, and im-
paired leptin responsiveness that exacerbates overnutrition-
induced weight gain. These 2 effects appear to be mediated
by different hypothalamic mechanisms, and both may be as-
sociated with fructose-induced energy overconsumption
and weight gain.
ã2012 American Society for Nutrition. Adv. Nutr. 3: 736–738, 2012; doi:10.3945/an.112.002659.
Carbohydrate-induced leptin resistance and its
potential metabolic basis
The next topic was presented by Ruth B Harris, Georgia
Health Sciences University, Augusta, GA. We previously
showed that rats offered the choice of nonpurified laboratory
diet, lard, and 30% sucrose solution increase their energy in-
take and rapidly become obese. They are also resistant to
both peripheral and central leptin administration after
only 16 d on the choice diet. The increase in energy intake
and body fat of rats offered sucrose solution and nonpurified
laboratory diet, but not lard (sucrose-fed rats), was not as
great as that of choice-fed rats, but leptin resistance is also
apparent in these animals after 25 d. Thus, leptin resistance
under these dietary conditions was associated with the con-
sumption of sucrose solution rather than obesity per se
or the consumption of fat. Phosphorylation of STAT3
(PSTAT3) in the arcuate nucleus (ARC) of the hypothalamus
is routinely used as a marker of leptin responsiveness. We
found that hypothalamic PSTAT3 was elevated under non-
stimulated conditions in the sucrose-fed rats and that leptin
injections did not increase PSTAT3 beyond these basal levels,
demonstrating the presence of central leptin resistance. Rats
offered a 30% sucrose solution consumed 50% of their en-
ergy as sucrose, which would increase activity of any pathway
that metabolizes glucose or fructose. One such pathway is
the hexosamine biosynthetic pathway (HBP). The product
of this pathway, UDP-N-acetylglucosamine, is the substrate
for O-glycan linked (O-linked) glycosylation of proteins and
transcription factors. Increased activity of the HBP is associ-
ated with development of insulin resistance due to glycosy-
lation of the insulin receptor and postreceptor signaling
proteins. Some of these proteins are the same as those re-
quired for leptin signaling; therefore, we are exploring the
possibility that consumption of sucrose solution leads to
O-linked glycosylation of leptin signaling proteins and leptin
resistance. Preliminary studies show that activation of the
HBP can cause leptin resistance and increase phosphoryla-
tion of hypothalamic STAT3 in a manner similar to that
seen in sucrose-fed rats. Glucosamine entry into the HBP
is not regulated and rats receiving continuous high doses
of glucosamine from i.p. miniosmotic pumps for 2 d were
resistant to a peripheral injection of leptin. In a second
study, rats were i.v. infused with glucosamine. The infusion
elevated blood glucose, indicative of the development of in-
sulin insensitivity. After 150 min, the rats were injected with
leptin and hypothalamic tissue was collected 30 min later.
Similar to the effects of sucrose consumption, glucosamine
infusion significantly increased PSTAT3 levels in the nonsti-
mulated state in the hypothalamus. Further investigation is
required to directly associate development of leptin resis-
tance in sucrose-fed rats with activity of the HBP and to de-
termine how O-linked glycosylation of specific proteins
interferes with leptin signaling.
The role of dietary TG in leptin resistance
Our third topic was presented by Joseph R Vasselli, Colum-
bia University, New York, NY. One potential mechanism
mediating leptin resistance was identified previously in a
study showing that acute infusion or injection of rats with
saturated TG blocks leptin transport across the blood brain
barrier (BBB), whereas the composite SFA administered as a
mixture are without any effect. Moreover, it has been shown
that whereas saturated fat fed to rats in a HFD quickly in-
duces obesity, this is not the case when polyunsaturated
fat is used. We tested the hypothesis that leptin resistance
can be induced in vivo by low-level administration of satu-
rated TG by gavage to rats maintained on nonpurified labo-
ratory diet, whereas polyunsaturated TG should not have this
effect. Administration of emulsified TG in small amounts
by gavage permits precise control of the amount of TG ad-
ministered, and avoids elevated body fat and leptin levels re-
sulting from HFD feeding. We administered 2 equi-energetic
TG emulsions varying in saturation level to rats by oral ga-
vage for a single day and, following a washout period, for 11
consecutive days. Cream (majority saturated TG) and fish
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oil (majority polyunsaturated TG) emulsions containing
8.26 MJ/L (2.0 kcal/mL) were administered to rats twice
daily in a volume of 1.0 mL (5% of total daily ingested en-
ergy). After both acute (1-d) and subchronic (11-d) TG ad-
ministration, the cream group was resistant to the feeding
inhibitory effects of injected leptin, whereas the fish oil
group was not. After a washout period, a saline gavage group
was added and the groups, while still maintained on a non-
purified laboratory diet, were gavaged for an additional 11 d.
Immediately following the gavage series, their intake of 45
and 60% HFD was each tested for 24-h periods. The cream
group ate significantly more HFD during both intake tests
than the other 2 groups. In a final study, again following a
washout period, the groups were gavaged for 18 additional
days while still being fed the nonpurified laboratory diet
and were then offered 45% HFD ad libitum for 12 d. The
cream group ate significantly more of the HFD and gained
significantly more body weight than the saline group over
the 12-d HFD access period, whereas the fish oil group did
not. These results indicate that administration of extremely
small amounts of saturated TG to normal-weight rats con-
suming a nonpurified laboratory diet can induce resistance
to the effects of injected leptin and elevate feeding in response
to a HFD both acutely and in the long term. The findings sup-
port the hypothesis that TG induce resistance to leptin trans-
port at the BBB, with saturation level being the critical factor.
Nutrient influences and mechanisms in
leptin resistance
Our final topic was presented by William A. Banks, Univer-
sity of Washington, Seattle, WA. Leptin resistance at the BBB
has several causes. As a first cause, the saturable nature of the
BBB transport of leptin limits the degree to which leptin can
enter and accumulate within the CNS. At levels seen in thin
animals, the relation between serum and cerebrospinal fluid
levels of leptin is near linear, but at levels seen in obese an-
imals, there is little increase in cerebrospinal fluid leptin
levels despite dramatic increases in serum leptin levels.
The flattening of the serum-CNS curve begins at relatively
Dietary factors in leptin resistance 737
low serum levels of leptin, perhaps around 300 pmol/L. This
means that the peripheral signal to the brain as mediated by
leptin is greatly attenuated in moderate obesity and perhaps
even at levels of adiposity generally thought to reflect ideal
body weight. Modulators of the leptin transporter are likely
also involved as a second cause of leptin resistance. The lep-
tin transport rate is modified by a number of factors, includ-
ing adrenergics, insulin, glucose, and TG. TG may be major
modulators of the blood-to-brain transfer of information
between the gut and brain as mediated by gastrointestinal
hormones. TG inhibit leptin transport in a dose-dependent
manner. They are apparently the mechanism, at least in part,
by which fasting and starvation modulate leptin transport
across the BBB, thus modifying the food-seeking behavior
of the animal. In this scenario, serum TG are elevated during
starvation, with the TG inhibiting the anorectic signal to the
brain as conveyed by leptin. Both TG and starvation stimu-
late the transport of insulin and ghrelin across the BBB.
Thus, TG, by modulating the influx of gastrointestinal hor-
mones into the brain, may be one of a host of circulating fac-
tors that help to determine feeding behavior. TG may also
affect other central actions of leptin. Recent work has shown
that TG in the serum and brain are correlated with cognitive
behavior. For example, obese mice have learning and mem-
ory deficits that can be reversed when they are treated with
738 Symposium
gemfibrozil, a drug that selectively decreases TG levels. Fur-
thermore, normal-weight mice given TG directly into the
brain have defects in memory. Together, these results show
that TG exemplify what is probably a general phenomenon:
that circulating substances modify behavior by their ability
to affect the blood-to-brain transport of hormones involved
in the gut-brain axis.
Conclusion
The above findings clearly demonstrate the saliency of spe-
cific dietary components in generating states of leptin resis-
tance, which in turn are capable of increasing energy intake
and elevating body weight gain under appropriate dietary
challenges. In addition, it appears that more than one poten-
tial biological mechanism may be associated with the dietary
induction of leptin resistance, including alterations in cen-
tral and peripheral metabolism and/or receptor signaling.
We need to learn much more about the generality of these
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phenomena in determining excess energy intake under com-
mon feeding conditions, such as multi-item diet selection
regimens characteristic of human feeding situations. What
is clear from the above findings is that diet-induced leptin
resistance can occur in the absence of elevated circulating
leptin levels and body fat, rendering it a potential predispos-
ing factor for excess body weight gain and obesity.