Robert H. Lustig, M.D., M.S.L.
Emeritus Professor, Division of Endocrinology
Department of Pediatrics
Institute for Health Policy Studies
University of California, San Francisco
Are our children being fruct?
Sugar on the brain
Smart Kids and Teens, Food for the Brain, April 26, 2025
Disclosures
Paid Advisor:
Simplex Health
Myka Labs
Levels Health
Chief Medical Officer:
BioLumen
Ireneo Health
Perfact
I will not be speaking about any of these companies or products
Unpaid Advisor:
Kuwaiti Danish Dairy
Blue Oak Nutriceuticals
Sugar
Srour et al. BMJ 365:l1451, 2019; Wang et al. JAMA 326:519, 2021
56% of the food sold in America is ultraprocessed food
Accounts for 62% of the sugar in the American diet
And 67% of the sugar in kids’ diets
The SFUSD School Milk Program
Courtesy of
M. Lustig
The SFUSD School Milk Program
Courtesy of
M. Lustig
The change in our global food supply
Addition of fructose
• palatability (esp. with decreased fat)
• browning agent
Removal of fiber
• shelf life
• freezing
High Fructose Corn Syrup is 42-55% Fructose;
Sucrose is 50% Fructose
Glucose
Fructose
Sucrose
Fructose is not glucose
• Fructose is 7 times more likely than glucose
to form Advanced Glycation End-Products (AGE’s)
• Fructose does not suppress ghrelin
• Acute fructose does not stimulate insulin (or leptin)
• Hepatic fructose metabolism is different in liver and brain
• Chronic fructose exposure promotes the metabolic syndrome,
including brain manifestations
Elliot et al. Am J Clin Nutr, 2002
Bray et al. Am J Clin Nutr, 2004
Teff et al. J Clin Endocrinol Metab, 2004
Gaby, Alt Med Rev, 2005
Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006
Wei et al. J Nutr Biochem, 2006
Johnson et al. Am J Clin Nutr 2007
Rutledge and Adeli, Nutr Rev, 2007
Brown et al. Int. J. Obes, 2008
Liver
(80%)
(100%)
Sugar effects on the brain:�mechanisms
1. CNS energy metabolism:�Mitochondrial dysfunction
Manji et al. Nat Rev Neurosci 2012
Fructose reduces liver mitochondrial function, while glucose stimulates it
Softic et al. Cell Metab 30:735, 2019
"The most important takeaway of this study is that high fructose in the diet is bad," says Dr. Kahn. "It's not bad because it's more calories, but because it has effects on liver metabolism to make it worse at burning fat. As a result, adding fructose to the diet makes the liver store more fat, and this is bad for the liver and bad for whole body metabolism."
Dr. C. Ronald Kahn,
CEO, Joslin Diabetes Center
Fructose and neuroinflammation�in astrocytes and microglia
Johnson et al. Front Aging Neurosci 2020 | https://doi.org/10.3389/fnagi.2020.560865
Fructose induces reprogramming of microglia �from M2 (anti-) to M1 (pro-inflammatory)
Ting et al. Front Immunology 2024 DOI 10.3389/fimmu.2024.1375453
2. CNS Neurotransmission:�Glutamate—Glutamine—GABA
In vivo magnetic resonance spectra in humans after infusion of glucose or fructose:�The human brain turns glucose into fructose
Hwang et al. JCI Insight 2:e90508, 2017
Fructose is Made in the in Brain in Response to Hyperglycemia
Hwang et al. JCI Insight. 2(4):e90508, 2017
Blood glucose raised to 220 mg/dl (12mM) for 4 hrs
CSF:blood ratio of glucose or fructose due to the �insulin resistance of pregnancy
Hwang et al. PLoS One 10(6): e0128582, 2015
DM
NL
Glutamine synthetase — �Glutamate to glutamine cycle in astrocytes
Hertz, Front Endocrinol 4:1, 2013
The relation between glutaminergic and GABA-ergic neurons is glutamine synthetase in astrocytes
Incubation of rat cortical synaptosomes with glucose or fructose
Fructose
Glucose
tamate
artate
tamate
artate
Hassel et al. J Neurochem 133:572, 2015
Jones et al. Nat Comm 12:1209, 2021
Fructose inhibits glutamine synthetase in immune cells
3. CNS Trophic effects:�Insulin—Leptin—BDNF
Ultra-processed food consumption correlates with depression
Gomez-Ronoso et al. Eur J Nutrition 2019 doi:10.1007/s00394-019-01970-1
Insulin resistance is a driver of depression
Watson et al. Neurophamacology 136:327, 2018
Leptin causes neurons to branch and connect
Lee, Ann. NY Acad Sci 1243:15, 2011
Leptin regulates neural and glial protein levels
Ahima et al. Endocrinology 140:2755, 1999
Leptin corrects cognitive defects in patients with leptin deficiency
Paz-Filho et al. PLoS One 3:e3098, 2008
Sugar causes insulin resistance, and
insulin resistance causes leptin resistance
Lim et al., Nat Rev Gastro Hepatol 7:251, 2010
Lustig, Nat Rev Endocrinol Metab 2:447, 2006
Insulin blocks leptin signaling in the brain
Exercise, BDNF, and depression
Erickson et al. Neuroscientist 18:82, 2012
4. CNS exposures:�Gut microbiome
Fructose affects the gut microbiome too
Silva et al. J Proteome Res 17:2880, 2018
Tight junctions keep bad stuff out
Di Ciaula et al. J Clin Med 9:2648 2020
Fructose disrupts tight junctions, �and lets bad stuff in
Cho et al. Hepatology 2019 Apr 8. doi: 10.1002/hep.30652.
Sugar alters Th17 barrier in the intestine
Kawano et al., Cell 185, 1, 2022
Group A Streptococcus grow better with fructose than glucose
Dmitriev et al. J Bacteriol 188:7230, 2006
GAS responsible for
psych disease:
OCD
tic disorders
adult personality dis.
mood disorder
Orlovska et al. JAMA Pediatr. 74:740, 2017
5. Addiction
(Reuters) March 28, 2010 - Bingeing on high-calorie foods
may be as addictive as cocaine or nicotine, and could cause
compulsive eating and obesity, according to a study
published on Sunday.
Junk food addiction may be clue to obesity: study
Johnson and Kenny, Nat Neurosci 2010
Sugar and opioids
Sweet-Ease increases endogenous opioids to reduce pain,
Even in neonates
PLoS One 10(6):e0130280, 2014
No satiety or fullness with fructose compared with glucose
No insulin rise with fructose compared with glucose
fMRI:
Glucose: caudate, putamen, precuneus, lingual gyrus
Fructose: amygdala, hippocampus, parahippocampus, orbitofrontal cortex
precentral gyrus
Fructose Increases Hunger, Desire for Food, Increases Visual Cues, Reduces Will Power, and Reduces Recent Memory
Fructose Increases Visual Cortex Activity To Food Cues With More Hunger And Desire For Food
Fructose Decreases Cortical Activity Involved In Self Control
(Glucose Does Opposite)
Fructose Decreases Blood Flow To Hippocampus
Luo et al PNAS. 2015;112:6509
Purnell et al Diabetes Obes Metab. 2011;13:229
Page et al JAMA. 2013;309:63
Glucose
Fructose
Ultraprocessed food promotes tolerance and withdrawal
Adults
Depression
Mental Health:�Ultraprocessed food and depression
Global Mind Project (n = 227,000)
Cognitive Decline
22 Symptoms of Carbohydrate-Associated Reversible Brain (CARB) syndrome
Wilson, Brain Drain 2020
Ultraprocessed food inhibits cognition in older adults
Cardoso et al. Eur J Nutr online July 1, 2022
Pase et al Alzheimers Dement.13:955, 2017
Liu et al. Nutr Neuroscience 25:2302, 2022
Sugar consumption correlates with dementia, as well as other systemic diseases
Does sugar cause dementia?
Obesity is associated with dementia
Luchsinger et al. J Alz Dis Assoc Dis 2011
Obesity is associated with altered
neural projections c/w dementia
Bouret et al. Cell Metab 7:179, 2008
Sugar generates insulin resistance
and hyperinsulinemia
Seneff et al. Eur J Int Med 22:134, 2011
Insulin resistance and high insulin
levels are associated with dementia
Craft et al. Nat Rev Neurol 8:360, 2012
Western Diet correlates with dementia
Barberger-Gateau et al. Neurology 69:1921, 2007
Fat or sugar both cause obesity in rats,
but only sugar caused cognitive decline
Jurdak et al. Nutr Neurosci 11:48, 2008
Causative data in animals; but to date
no direct associative or causative data in humans
Stephan et al. J Gerontol 65:809, 2010
Gomez-Pinilla, Nat Rev Neurosci 9:568, 2012
Hydrogen
peroxide
Anything that increases ROS production
can damage cells and result in cognitive decline
Agrawal et al J Cereb Blood Flow Metab. 2016; 36:941
Effect of Dietary Fructose on the Rat Brain
Agrawal and Gomez-Pinilla, J Physiol 590.10:2485, 2012
Insulin resistance, especially in the absence of omega-3’s, means lack of neuron signaling
Mohamed et al Food Biochem. 2021;45:e13715, 2021
and Nutr Seurosci, 23:1, 27-36: 2020
Dietary Fructose Increases Amyloid and Tau Protein in the Brain of Rats
Amyloid (Congo Red Positive)
Tau Protein (Brown Stain)
Control
Control
Fructose
Fructose
Fructose
High Fructose Levels and Low ATP in the Brains of Alzheimer’s Patients
Xu et al Sci Rep. 2016 Jun 9;6:27524
CALCULATED BRAIN ATP FORMATION RATE (UMOL/G/MIN)
Kids
Reduced hippocampus but more CSF�in adolescents with metabolic syndrome
Yau et al. Pediatrics 130:e856, 2012
Reduced prefrontal cortical function�in adolescents with metabolic syndrome
Yau et al. Pediatrics 130:e856, 2012
The ‘Twinkie Defense’:
Relationship between carbonated non-diet soft drinks and violence perpetration among Boston high school students
Adolescents who drank more than five cans of soft drinks per week (30%):
• more likely to have carried a weapon
• violent with peers, family members and dates.
•even after controlling for gender, age, race, BMI, sleep, tobacco use, alcohol use, and family dinners.
Solnick and Hemenway, Inj Prev 18:259, 2012
Beecher et al. Front Neurosci 15 : 670430, 2021
Suglia et al. J. Pediatr. 163: 1323-1328, 2013
Babies
Young children prefer sweet
Bobowski and Mennella, Child Obes 13:369, 2017
Commercial infant foods and health claims
Koo et al. PLoS One 13:e0191982, 2018
Could this be the reason for obesity in�6-month olds?
INGREDIENTS (Powder)
((U) Pareve*)
43.2% Corn syrup solids,
14.6% soy protein isolate,
11.5% high oleic safflower oil,
10.3% sugar (sucrose),
8.4% soy oil,
8.1% coconut oil
Courtesy of M. Walker
Could this be the reason for obesity in�6-month olds?
INGREDIENTS (Powder)
((U) Pareve*)
43.2% Corn syrup solids,
14.6% soy protein isolate,
11.5% high oleic safflower oil,
10.3% sugar (sucrose),
8.4% soy oil,
8.1% coconut oil
Courtesy of M. Walker
Coca-Cola:10.5% sucrose (fiberless)
Milk shake:4% sucrose (fiberless)
Breast Milk:7.1% lactose (fiberless),
no sucrose, EXCEPT:
Fructose in breast milk predicts weight and fat mass at 6 mos of age
Goran et al. Nutrients 9:146, 2017
Fetuses
(2010)
Chiu
Postulated effect of maternal fructose consumption on the offspring
Goran et al. Nat Rev Endocrinol 9:494, 2013
Experimental maternal fructose ingestion:�effects on the placenta
Asghar et al. Sci Rep 6:25091, 2016
Experimental maternal fructose ingestion:�effects on the offspring
Rodriguez et al. J Nutr Biochem 24:1709, 2013
Chiu et al. JAMA Network Open 7:e2422749, 2024
Sugar and epigenetics
UK sugar rationing ended in 1953—�offspring born after rationing with higher diabetes and hypertension
Gracner et al., Science 10.1126/science.adn5421, 2024
Untested hypothesis: fructose alters epigenetics to alter prenatal brain development
Dufault et al. World J Clin Pediatr 12:25, 2023
New York Times,
April 17, 2011
Nature 487:27-29,
Feb 1, 2012
Summary