The prevalence of obesity began to rise rapidly in the 1980s and since then has more than doubled (1). Sugar (2), sugar-sweetened beverages, and the fructose that they provide have been consistently linked to the risk for obesity (3). Ludwig, Peterson, and Gortmaker (4) provided one of the earliest suggestions that intake of sugar-sweetened beverages might predict weight gain, and this has been supported by an increasing number of studies (5). Because foods can activate the “pleasure” center circuitry, the same circuitry that is activated by drugs of abuse and alcohol (6), the suggestion that sugar might be “addictive” has surfaced from time to time (7,8).

The study by Jastreboff et al. in this issue of Diabetes (9), and an earlier pilot study (10), using functional MRI after oral ingestion of either glucose or fructose in 14 lean and 24 adolescents with obesity extends our knowledge of how these hexoses act on the brain. In the lean adolescents, both glucose and fructose increased perfusion of brain areas involved in “executive function and control” (prefrontal cortex) (Fig. 1) but did not activate the “homeostatic” appetite control areas (hypothalamus). A very different picture was seen in the adolescents with obesity where ingestion of either fructose or glucose reduced perfusion of the executive region of the brain (prefrontal cortex) and increased activity in the “reward” or “pleasure” centers. This suggests that obese adolescents may lack the ability to downregulate the hedonic and homeostatic regions of the brain after oral ingestion of fructose or glucose. In addition, the ingestion of fructose produced a greater increase in perfusion of the pleasure or reward centers in the adolescents with obesity—something not seen in the lean adolescents. The authors speculate that the reduced response of the executive centers to fructose/glucose may reduce their ability to control intake of sugar-sweetened beverages.

Figure 1

Signaling in the brain of adolescents in response to glucose or fructose: schematic representation of changes in the periphery and brain after the ingestion of glucose or fructose. Subjective responses using variable analog scales (VAS) are shown in the lower-left corner for hunger, fullness, and satiety where differences were detected. Both glucose and fructose are absorbed, but fructose is largely cleared in the liver, where it stimulates de novo lipogenesis. Glucose is taken up by many tissues and stimulates insulin release from the pancreas more so in the adolescents with obesity than in lean adolescents. Both monosaccharides reduce circulating acyl-ghrelin concentrations. Effects of glucose and fructose on cerebral blood flow relative to baseline are shown by arrows in major regions of the brain: the prefrontal cortex, which has major executive functions; the hypothalamus, which modulates appetite; and the limbic system and striatum-thalamus, which encompass the reward feature of food. Solid lines represent neural connections and dashed lines circulating connections. ‡Adjusted for acyl-ghrelin and insulin. ACC, anterior cingulate cortex; F, fructose; Fru, fructose; G, glucose; GLP-1, glucagon like peptide 1; L, lean adolescents; N. accumbens, nucleus accumbens; Ob, adolescents with obesity; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, polypeptide YY; TG, triglyceride.

Figure 1

Signaling in the brain of adolescents in response to glucose or fructose: schematic representation of changes in the periphery and brain after the ingestion of glucose or fructose. Subjective responses using variable analog scales (VAS) are shown in the lower-left corner for hunger, fullness, and satiety where differences were detected. Both glucose and fructose are absorbed, but fructose is largely cleared in the liver, where it stimulates de novo lipogenesis. Glucose is taken up by many tissues and stimulates insulin release from the pancreas more so in the adolescents with obesity than in lean adolescents. Both monosaccharides reduce circulating acyl-ghrelin concentrations. Effects of glucose and fructose on cerebral blood flow relative to baseline are shown by arrows in major regions of the brain: the prefrontal cortex, which has major executive functions; the hypothalamus, which modulates appetite; and the limbic system and striatum-thalamus, which encompass the reward feature of food. Solid lines represent neural connections and dashed lines circulating connections. ‡Adjusted for acyl-ghrelin and insulin. ACC, anterior cingulate cortex; F, fructose; Fru, fructose; G, glucose; GLP-1, glucagon like peptide 1; L, lean adolescents; N. accumbens, nucleus accumbens; Ob, adolescents with obesity; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, polypeptide YY; TG, triglyceride.

After absorption, fructose is largely cleared by the liver, leaving only small circulating concentrations. The intriguing question is how fructose produces these effects in the brain. Jastreboff et al. (9) suggest a possible mechanism through changes in the active form of ghrelin (acyl-ghrelin) with a contribution from the higher insulin in the obese. After ingestion of glucose, acyl-ghrelin is significantly suppressed by glucose and more so by fructose in the adolescents with or without obesity. However, circulating levels are higher in the lean than the obese. Changes in ghrelin might provide a signal for the changes in perfusion in various brain regions. Insulin, which responds to glucose, may also play a role through its central nervous system receptors, since the relative increase of insulin in the adolescents with obesity was much greater than in the lean adolescents. However, changes in insulin with fructose were very small, suggesting that lowering of acyl-ghrelin may be a more important messenger for control of central behavior and activation of the pleasure center.

Understanding how adolescents who are obese differ from those who are not is important in framing preventive strategies. The study by Jastreboff et al. (9) describes functional differences in the central nervous system during response to fructose or glucose solutions. First, the executive center in the prefrontal cortex is inhibited in the obese, confirming earlier work in adolescents (11,12) and adults where Volkow et al. (13) showed a significant negative correlation between BMI and metabolic activity in prefrontal cortex and cingulate gyrus. Using leptin as a surrogate for fatness, Jastreboff et al. (9) found that it was inversely related to blood flow in the prefrontal cortex. Second, the hypothalamus, which plays a key role in the homeostatic regulation of food intake, is activated by glucose/fructose in the adolescents with obesity but not in the lean, a change that might stimulate feeding in those with obesity. The pleasure or reward centers in the limbic system and striatum are also activated by fructose/glucose in adolescents with obesity. Much evidence supports the hypothesis that the arcuate hypothalamus plays a direct role in ghrelin-regulated homeostatic feeding and that the ventral tegmental area directly mediates ghrelin-induced hedonic eating (14).

This is a cross-sectional study and leaves at least one key question unanswered: Which came first, the obesity or the changes in brain response? The idea that sugar might be addictive or habituating surfaced over 40 years ago (7,8), in part related to the finding that endogenous opioids (endorphin and enkephalin) stimulate feeding, as do endogenous cannabinoids, which were identified after noting that “marihuana” stimulated feeding.

In addition to the association of sugar (glucose/fructose) intake with the risk for developing obesity, diabetes, and heart disease, fructose seems to have other possibly detrimental metabolic effects (15,16). Fructose stimulates de novo lipogenesis and liver fat (17), increases visceral adipose tissue (16), and increases triglyceride levels (15). Drinking sugar-sweetened beverages for 6 months can replicate the findings of the metabolic syndrome (18). Both glucose and fructose provide energy, but fructose in addition provides a more intense sweetness than glucose and, as shown in the study by Jastreboff et al. (9), stimulates the striatal complex, which may provide a hedonic override of the homeostatic control of feeding (19).

Evidence supporting features of addiction to sucrose come mainly from studies in experimental animals (7). Withdrawal from a “sugar-rich” diet is associated with behavior suggestive of “withdrawal” symptoms. Clinical support for this idea comes from a study by Drewnowski et al. (20), who used naloxone to block opioid receptors in women who were binge eaters and those who were not. In the binge eaters, naloxone reduced the preference for sweet taste and the actual amounts consumed. The findings of Jastreboff et al. (9) that glucose and fructose stimulate the striatal system more in the adolescents with obesity than in lean individuals indicate that these molecules have addictive or habituating potential. In many cases sucrose is consumed in sugar-sweetened beverages that also contain caffeine, a drug that stimulates the central nervous system. It would be of great interest to find out whether caffeine added to the glucose or fructose produced more profound effects on the striatal system of adolescents with obesity.

See accompanying article, p. 1929.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
Ng
M
,
Fleming
T
,
Robinson
M
, et al
.
Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013
.
Lancet
2014
;
384
:
766
781
[PubMed]
2.
Yang
Q
,
Zhang
Z
,
Gregg
EW
,
Flanders
WD
,
Merritt
R
,
Hu
FB
.
Added sugar intake and cardiovascular diseases mortality among US adults
.
JAMA Intern Med
2014
;
174
:
516
524
[PubMed]
3.
Bray
GA
,
Popkin
BM
.
Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes? Health be damned! Pour on the sugar
.
Diabetes Care
2014
;
37
:
950
956
[PubMed]
4.
Ludwig
DS
,
Peterson
KE
,
Gortmaker
SL
.
Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis
.
Lancet
2001
;
357
:
505
508
[PubMed]
5.
Malik
VS
,
Popkin
BM
,
Bray
GA
,
Després
JP
,
Hu
FB
.
Sugar-sweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk
.
Circulation
2010
;
121
:
1356
1364
[PubMed]
6.
Lustig
RH
.
Fructose: metabolic, hedonic, and societal parallels with ethanol
.
J Am Diet Assoc
2010
;
110
:
1307
1321
[PubMed]
7.
Avena
NM
,
Rada
P
,
Hoebel
BG
.
Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake
.
Neurosci Biobehav Rev
2008
;
32
:
20
39
[PubMed]
8.
Hebebrand
J
,
Albayrak
Ö
,
Adan
R
, et al
.
“Eating addiction”, rather than “food addiction”, better captures addictive-like eating behavior
.
Neurosci Biobehav Rev
2014
;
47
:
295
306
[PubMed]
9.
Jastreboff
AM
,
Sinha
R
,
Arora
J
, et al
.
Altered brain response to drinking glucose and fructose in obese adolescents
.
Diabetes
2016
;
65
:
1929
1939
10.
Page
KA
,
Chan
O
,
Arora
J
, et al
.
Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways
.
JAMA
2013
;
309
:
63
70
[PubMed]
11.
Maayan
L
,
Hoogendoorn
C
,
Sweat
V
,
Convit
A
.
Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction
.
Obesity (Silver Spring)
2011
;
19
:
1382
1387
[PubMed]
12.
Reinert KR, Po'e EK, Barkin SL. The relationship between executive function and obesity in children and adolescents: a systematic literature review. J Obes. 2013;2013:820956
13.
Volkow
ND
,
Wang
GJ
,
Telang
F
, et al
.
Inverse association between BMI and prefrontal metabolic activity in healthy adults
.
Obesity (Silver Spring)
2009
;
17
:
60
65
[PubMed]
14.
Mason
BL
,
Wang
Q
,
Zigman
JM
.
The central nervous system sites mediating the orexigenic actions of ghrelin
.
Annu Rev Physiol
2014
;
76
:
519
533
[PubMed]
15.
Bray
GA
.
Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people
.
Adv Nutr
2013
;
4
:
220
225
[PubMed]
16.
Stanhope
KL
,
Schwarz
JM
,
Havel
PJ
.
Adverse metabolic effects of dietary fructose: results from the recent epidemiological, clinical, and mechanistic studies
.
Curr Opin Lipidol
2013
;
24
:
198
206
[PubMed]
17.
Schwarz
JM
,
Noworolski
SM
,
Wen
MJ
, et al
.
Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat
.
J Clin Endocrinol Metab
2015
;
100
:
2434
2442
[PubMed]
18.
Maersk
M
,
Belza
A
,
Stødkilde-Jørgensen
H
, et al
.
Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study
.
Am J Clin Nutr
2012
;
95
:
283
289
[PubMed]
19.
Bray
GA
.
Obesity: A failure of homeostasis due to hedonic rewards: Response to the letter from Gary Taubes
.
Obes Rev
2008
;
10
:
99
102
20.
Drewnowski
A
,
Krahn
DD
,
Demitrack
MA
,
Nairn
K
,
Gosnell
BA
.
Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters
.
Am J Clin Nutr
1995
;
61
:
1206
1212
[PubMed]