Clinical MedicineNeuroscience Open Access | 10.1172/jci.insight.175967

Guanya Li,1,2 Yang Hu,1,2 Wenchao Zhang,1,2 Jia Wang,1,2 Lijuan Sun,3 Juan Yu,4 Peter Manza,5 Nora D. Volkow,5 Gang Ji,4 Gene-Jack Wang,5 and Yi Zhang1,2

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

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1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

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1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

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1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Wang, J. in: JCI | PubMed | Google Scholar

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Sun, L. in: JCI | PubMed | Google Scholar

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Yu, J. in: JCI | PubMed | Google Scholar

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

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1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Volkow, N. in: JCI | PubMed | Google Scholar

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Ji, G. in: JCI | PubMed | Google Scholar

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Wang, G. in: JCI | PubMed | Google Scholar |

1Center for Brain Imaging, School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xi’an, Shaanxi, China.

2International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment and Xi’an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi’an, Shaanxi, China.

3Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China.

4Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China.

5Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.

Address correspondence to: Yi Zhang, Center for Brain Imaging, School of Life Science and Technology, Xidian University & Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, No. 266 Xifeng Road, Xi’an, Shaanxi 710126, China. Phone: 86.29.81891070; Email: yizhang@xidian.edu.cn. Or to: Gene-Jack Wang, Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, MSC1013, Building 10, Room B2L304, Bethesda, Maryland 20892-1013, USA. Phone: 1.301.496.5012; Email: gene-jack.wang@nih.gov. Or to: Gang Ji, State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, No. 127 Changle West Road, Xi’an, Shaanxi 710032, China. Phone: 86.29.84771620; Email: jigang@fmmu.edu.cn.

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Find articles by Zhang, Y. in: JCI | PubMed | Google Scholar

Authorship note: GL, YH, and WZ contributed equally to this work and are co–first authors.

Published August 1, 2024 - More info

Published in Volume 9, Issue 17 on September 10, 2024
JCI Insight. 2024;9(17):e175967. https://doi.org/10.1172/jci.insight.175967.
© 2024 Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published August 1, 2024 - Version history
Received: September 20, 2023; Accepted: July 25, 2024 View PDF Abstract

BACKGROUND. A polymorphism in the fat mass and obesity-associated gene (FTO) is linked to enhanced neural sensitivity to food cues and attenuated ghrelin suppression. Risk allele carriers regain more weight than noncarriers after bariatric surgery. It remains unclear how FTO variation affects brain function and ghrelin following surgery.

METHODS. Resting-state functional magnetic resonance imaging and cue-reactivity functional magnetic resonance imaging with high-/low-caloric food cues were performed before surgery and at 1, 6, and 12 months after surgery to examine brain function in 16 carriers with 1 copy of the rs9939609 A allele (AT) and 26 noncarriers (TT). Behavioral assessments up to 5 years after surgery were also conducted.

RESULTS. The AT group relative to the TT group had smaller BMI loss at 12–60 months after surgery and lower resting-state activity in posterior cingulate cortex following laparoscopic sleeve gastrectomy (group-by-time interaction effects). Meanwhile, the AT group relative to the TT group showed greater food cue responses in dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and insula (group effects). There were negative associations of weight loss with ghrelin and greater activation in DLPFC, DMPFC and insula in the AT but not the TT group.

CONCLUSION. These findings indicate that FTO variation is associated with the evolution of ghrelin signaling and brain function after bariatric surgery, which might hinder weight loss.

TRIAL REGISTRATION. Chinese Clinical Trial Registry Center, ChiCTR-OOB-15006346.

FUNDING. This work was supported by the National Natural Science Foundation of China (grant nos. 82172023, 82202252, 82302292); National Key R&D Program of China (no. 2022YFC3500603); Natural Science Basic Research Program of Shaanxi (grant nos. 2022JC-44, 2022JQ-622, 2023-JC-QN-0922, 2023-ZDLSF-07); Fundamental Research Funds for the Central Universities (grant nos. ZYTS23188, XJSJ23190, XJS221201, QTZX23093); and the Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse (grant no. Y1AA3009).

Introduction

Obesity results from the imbalance between energy intake and expenditure combined with genetic susceptibility (1). The fat mass and obesity-associated gene (FTO) is a well-replicated gene locus of obesity across different ages and populations. A cluster of single nucleotide polymorphisms (SNPs) within intron 1 of FTO have been consistently associated with higher BMI and increased food intake (2). The rs9939609 A allele is one of the strongest risk factors for polygenic obesity, and this variant has population frequencies of 46% in Western and Central Europeans, and 16% in Chinese individuals (3). Carriers of two copies of the risk-conferring variant had a 1.67-fold increased risk of obesity relative with noncarriers (4). Although the rs9939609 A allele frequency is lower in Chinese populations compared with European populations, the FTO SNPs are strongly associated with obesity risk in the Chinese population (5).

FTO encodes an RNA adenosine demethylase that catalyzes the oxidative demethylation of N6-methyladenosine (m6A) (6, 7). Considerable epigenetic research showed that FTO-mediated m6A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism (7). Furthermore, FTO has highest expression in the brain in humans, particularly in the cerebral cortex (4). Allelic variants in FTO modulate brain responses to food cues in regions involved in satiety (hypothalamus), food reward (ventral tegmental area [VTA] and nucleus accumbens), and inhibitory control of eating (prefrontal cortex), thereby enhancing neural sensitivity to food stimulation and increasing food intake (8, 9). In addition, FTO variants are linked to higher plasma levels of the hunger hormone ghrelin. Individuals homozygous for the rs9939609 A allele display an attenuated postprandial suppression of orexigenic hormone acyl-ghrelin compared with individuals homozygous for the low-risk T allele (10), which predisposes FTO variant carriers to higher energy intake and, consequently, higher fat mass (10).

The FTO genotype has also been associated with individual variability in weight loss in response to multiple obesity treatment methods, including diet, lifestyle interventions, physical exercise, and bariatric surgery (11–14). Laparoscopic sleeve gastrectomy (LSG), one of the most effective bariatric surgical procedures, produces sustained weight loss and reduces craving for high-calorie food after surgery (15). However, there is also a lower proportion of weight loss in individuals carried the rs9939609 A allele, with a greater and earlier weight regain 2 years after LSG in European population (16, 17). There might be significant effects of the rs9939609 genetic variant on weight loss in Chinese populations due to the similar effects of the FTO variant on obesity in both Western and Chinese populations (5), but the long-term evaluation is still lacking. At the same time, a better understanding of the modification effects of genetic variation on weight loss in response to LSG may help to develop more effective individualized strategies for obesity treatment.

Therapeutic benefits of LSG are partly mediated through its actions on the brain. The reduced appetite seen after surgery has been attributed to changes in functional and structural frontal-mesolimbic circuitry that regulate appetite, reward, and incentive motivation (18). After LSG, participants with obesity showed significant increased gray matter density/volume in the caudate, insula, hippocampus, amygdala, anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC) and decreased activation in response to food cues in the striatum, VTA, and dorsolateral prefrontal cortex (DLPFC), which correlated with reduced food craving and weight loss (19). It remains unclear how the FTO gene polymorphism affects LSG-induced changes in brain function. It is possible that individuals carried the high-risk allele would retain high neural sensitivity to food cues after LSG, resulting in smaller weight loss and greater weight regain.

LSG involves removal of the gastric fundus where ghrelin is mainly produced. There were significant decreases in fasting plasma ghrelin levels after LSG, which were associated with less craving for high-calorie food cues and reduced DLPFC activation (19, 20) along with strengthened functional and structural connectivity with ventral ACC, a region important for self-control and executive functions (21, 22). Ghrelin was also associated with hippocampal function through its modulation of connectivity with the insula (23). These studies indicate that changes in ghrelin play an important role in regulation of energy homeostasis and weight loss following surgery in part through its actions in limbic, interoceptive, executive, and saliency brain regions (18). FTO overexpression reduced ghrelin mRNA m6A methylation, concomitantly increasing ghrelin mRNA and peptide levels (10), which implies that FTO variants may also have an effect on the evolution of ghrelin levels following surgery.

Here, we employed resting-state functional magnetic resonance imaging (RS-fMRI) to examine the amplitude of low-frequency fluctuations (ALFF), a measurement of the spontaneous fluctuation in blood oxygen level–dependent fMRI (BOLD-fMRI) signal intensity that has been investigated as a reliable biomarker for many neurological conditions and obesity (24). The cue-reactivity fMRI task with high caloric (HiCal) and low caloric (LoCal) food cues was also performed to evaluate the effect of the rs9939609 A allele on brain function following LSG. Functional connectivity analyses were performed to assess whole-brain effects of the FTO variant. Fasting blood samples were collected to measure the plasma concentrations of total ghrelin as well as other hormones involved in appetite control and metabolism, including GLP-1, glucagon, leptin, and insulin. We also conducted BMI measurements up to 5 years after surgery. We hypothesized that FTO variant carriers compared with noncarriers would have higher ghrelin levels and neural activation in regions involved with reward and inhibitory control of eating following surgery and that these factors would be associated with long-term outcomes of bariatric surgery.

Results

Participant characteristics. Forty-two patients completed MRI assessments before surgery (PreLSG) and at 1, 6, and 12 months (PostLSG-1, -6, and -12) after surgery. All participants were also followed up at 24, 36, 48, and 60 months (PostLSG-24, -36, -48, and -60) after surgery and reported their BMI. Sixteen carriers with 1 copy of the rs9939609 A allele were classified as the AT group and 26 noncarriers were classified as the TT group. The rs9939609 A allele frequency of the current study population was 19.05%, which was 38.10% for the heterozygote and 0% homozygote of the A allele. A designated clinician rated anxiety and depression using the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD). Participants completed the Yale Food Addiction Scale (YFAS) evaluation to assess addictive eating behaviors. At baseline, there were no significant differences in age, sex, BMI, HiCal and LoCal food craving, and scores on the YFAS, HAMD, and HAMA questionnaires between AT and TT groups (Table 1 and Figure 1).

Figure 1

ANOVA showed significant interaction (group × time) effects on BMI and time effects on plasma ghrelin. (A) In the TT group, basal BMI was significantly correlated with BMI reductions at 12 months after LSG. (B) In the AT group, ghrelin plasma was increased at PostLSG-12, and levels were negatively correlated with BMI at 12 months after LSG.

Table 1

Demographic and clinical information of the AT and TT groups

ANOVA showed significant group × time interaction effects on weight (F = 4.91, P < 0.001) and BMI (F = 5.25, P < 0.001) and the percentage of excess BMI loss (EBMIL) (F = 5.17, P < 0.001). Post hoc tests showed that the TT group relative to the AT group had greater EBMIL (t = 2.26, P = 0.029, Cohen’s d = 0.72) and lower BMI (t = –2.44, P = 0.019, Cohen’s d = 0.77) at 12 months after LSG. Both the AT and TT groups showed significant weight regain starting 36 months after surgery; however, there was lower EBMIL in the AT group (Figure 1A). In the TT group, basal BMI was positively correlated with reduced BMI at 12 months after LSG (r = 0.84, P < 0.001) (Figure 1A) as well as 24, 36, 48, and 60 months following surgery (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.175967DS1), such that the higher the baseline BMI the greater the weight reduction. Meanwhile, the correlations between basal BMI and BMI reductions following LSG in the AT group were not significant (Figure 1A). In addition, we also evaluated the association between other previously reported single nucleotide polymorphisms (SNPs) of FTO gene (rs8050136, rs17817449, rs1421085, and rs1121980) and Mc4-R gene (rs17782313 and rs12970134) and the BMI loss following LSG. There were similar higher BMIs in FTO rs8050136, rs17817449, rs1421085, and rs1121980 variant carriers at 12 months after LSG due to the tight linkage disequilibrium with the FTO rs9939609 variant (Supplemental Tables 1 and 2). However, MC4-R variant carriers did not show group difference in BMI with noncarriers (Supplemental Table 2).

The interaction effect was not significant, but there were significant time effects on waist circumference (F = 202.08, P < 0.001), glucose (F = 26.23, P < 0.001), HiCal food craving (F = 12.63, P < 0.001), YFAS (F = 25.19, P < 0.001), HAMA (F = 18.05, P < 0.001), and HAMD (F = 8.30, P < 0.001) (Supplemental Table 3). There were significantly positive correlations between changes in HAMD and BMI loss at PostLSG-12 in the TT group (r = 0.42, P = 0.021) but not in the AT group (r = –0.22, P = 0.423). In the AT group, there were negative correlations between HiCal food craving at PostLSG-12 and EBMIL at 12, 24, 36, 48, and 60 months after LSG in the AT group (Supplemental Figure 2).

Peripheral hormone measurements. At baseline, there were no significant differences between the AT and TT groups in hormone measurements. LSG significantly decreased fasting plasma ghrelin (F = 37.97, P < 0.001), insulin (F = 14.81, P < 0.001), and leptin levels (F = 61.95, P < 0.001), but there were no significant group differences between the AT and TT groups. (Figure 1B). There were no significant time effects or group effects on glucagon and GLP-1 levels (Supplemental Tables 3 and 4). In the AT group, basal plasma ghrelin levels were negative correlated with BMI loss at PostLSG-6 (r = –0.52, P = 0.038) and PostLSG-12 (r = –0.57, P = 0.020). After LSG, ghrelin plasma in the AT group was increased at PostLSG-12 (t = 4.92, P < 0.001, Cohen’s d = 1.23) and levels were negatively correlated with BMI at 12 months (r = –0.55, P = 0.026) after LSG (Figure 1B) as well as 24, 36, 48, and 60 months following surgery (Supplemental Figure 3).

Resting-state brain activity. ALFF analysis was carried out to measure spontaneous fluctuations in resting-state BOLD fMRI signal intensity. ANOVA showed significant interaction effects of group on ALFF in PCC (Table 2 and Figure 2). Specifically, LSG increased PCC activity in the TT group at PostLSG-1, -6, and -12. Conversely, the AT group showed decreased ALFF in the PCC at PostLSG-12, which was significantly lower than that in the TT group (t = –4.897, P < 0.001, Cohen’s d = 1.56). The percentage of EBMIL in the AT group was negatively correlated with PCC activity at PostLSG-12 (r = –0.52, P = 0.038) (Figure 2). There were significant (P < 0.001) group effects on ALFF in orbitofrontal cortex (OFC), ACC, and PCC. The AT group showed lower activities in PCC and higher activities in OFC and ACC (Table 2). There were also significant (P < 0.001) time effects on ALFF in VTA, hippocampus/amygdala, and precentral/postcentral gyrus (PreCen/PostCen). Post hoc tests showed that LSG reduced VTA and hippocampus/amygdala activities and increased PreCen/PostCen activities (Table 2).

Figure 2

ANOVA showed significant interaction (group × time) effects on resting-state brain activity in PCC. PCC activity increased following LSG in the TT group at PostLSG-1, -6, and -12. Conversely, the AT group showed decreased ALFF in the PCC at PostLSG-12. BMI and the percentage of excess BMI loss (EBMIL) at 12 months after surgery in the AT group were correlated with PCC activity at PostLSG-12.

Table 2

Interaction and main effects of ANOVA for brain activities and responses to food cues (cluster size–corrected, PFWE < 0.05)

Brain responses to food cues. The general-linear model, including HiCal and LoCal food cue condition regressors, was constructed to evaluate how the brain responded to HiCal versus LoCal food cues. There were no significant time or interaction effects, but there were significant (P < 0.001) group effects on brain responses to HiCal versus LoCal food cues (Table 2). The AT compared with the TT group showed greater activation before and after surgery in the DLPFC, dorsomedial prefrontal cortex (DMPFC), insula, supplemental motor area (SMA), and postcentral gyrus (PFWE < 0.05, cluster-level correction) (Table 2 and Figure 3). BMI reductions in the AT group were negatively correlated with food cue–induced activation in DLPFC (r = –0.56, P = 0.022), insula (r = –0.55, P = 0.027), and DMPFC (r = –0.57, P = 0.021) at PostLSG-12 (Figure 3).

Figure 3

ANOVA showed group effects on brain responses to HiCal versus LoCal food cues. BMI reductions in the AT group were negatively correlated with food cue–induced activation in DLPFC, insula, and DMPFC at PostLSG-12.

Resting-state functional connectivity and PPI connectivity. There were no significant interaction effects on the resting state functional connectivity; however, there were significant group effects for the brain connectivity of PCC-DLPFC and PCC–angular gyrus. The post hoc tests showed that the AT group relative to the TT group has lower functional connectivity before and after surgery (Supplemental Table 3 and Supplemental Figure 4). There were significant group effects for the psychophysiological interaction connectivity (PPI) connectivity of DLPFC-hippocampus and DMPFC-caudate in response to HiCal versus LoCal food cues. The post hoc tests showed that the AT group relative to the TT group has greater PPI connectivity before and after surgery (Supplemental Table 5 and Supplemental Figure 4).

Discussion

Here we found that, compared with noncarriers, carriers of the rs9939609 A allele had less weight loss, lower resting-state activity in the PCC, and greater activation in the DLPFC, DMPFC, insula, SMA and postcentral gyrus following LSG. There were significant associations of weight loss with ghrelin, brain function, and food craving in the AT group, but none of these were significant in the TT group.

At baseline, there were no significant differences in BMI, food craving, and scores on the YFAS, HAMD, and HAMA questionnaires between the AT and TT groups. Individuals with obesity showed higher food craving and anxiety and depression levels compared with those of healthy-weight individuals. Both the AT and TT groups were at a similar raised weight status, which might prevent us from seeing difference by FTO genotype. After LSG, there was rapid weight loss in the first few months after surgery, likely due to purely restrictive and malabsorption mechanisms. Therefore, effects of rs9939609 FTO gene polymorphism on the magnitude of weight loss after LSG in the few months may not be noticeable (25). However, 36 months after surgery, A allele carriers of the rs9939609 FTO variant showed a lower proportion of surgery success and greater and earlier weight regain in Western populations (17). Our data showed that both the TT and AT groups achieved maximum weight loss at 12 months after LSG, and that the TT relative to the AT group had greater EBMIL and lower BMI, which indicated that FTO SNPs also play a vital role in weight change following LSG in Chinese populations. In the TT group, there was a significant positive correlation between baseline BMI and BMI loss at 12 months after LSG. This is consistent with results from previous reports showing that weight loss response was influenced by preoperative BMI, because people with higher BMI have more weight to lose. However, there was no similar association between baseline BMI and the smaller BMI loss in the AT group. In other words, individuals with the rs9939609 A allele had an attenuated weight loss response following LSG, especially among those with the highest BMI. At the same time, the rs9939609 A allele also affected weight regain outcomes in the long-term follow-up.

The FTO gene is associated with food intake regulation, and several lines of evidence indicate that A allele carriers exhibit higher craving for HiCal food and greater hunger, even in healthy-weight individuals (26). Although current results did not show a significant group difference in food craving between the AT and TT groups, there were negative correlations between craving for HiCal food cue at PostLSG-12 and EBMIL in the AT group, but not in the TT group, which suggests an interaction between the FTO genotype and eating behavior that impacts weight loss outcomes after LSG. The genetic predisposition of A allele carriers affects surgical outcomes, particularly when the initial restrictive effect decreases, resulting in smaller weight loss and more weight regain. Concomitantly, there were earlier rebound increases in plasma ghrelin in the AT group and ghrelin levels were negatively correlated with BMI at PostLSG-12. Ghrelin is the only known peripheral hormone that has orexigenic properties, stimulating appetite and increasing short-term food intake (27). Previous studies revealed that A allele carriers had impaired reduction in appetite-stimulating ghrelin levels, which was associated with more HiCal food craving after consuming a meal (10). The earlier rebound in ghrelin levels in the AT group relative to the TT group might promote parallel rebounds in food craving following LSG. Paradoxically, individuals with obesity show lower plasma ghrelin concentrations than the general population, which represent a physiological adaptation to the positive energy balance associated with obesity (27). LSG significantly decreases ghrelin due to the removal of the gastric fundus where ghrelin is mainly produced (18). The association between rebounding ghrelin and BMI at PostLSG-12 indicates a new adaptation to BMI, and the rising ghrelin levels might led to more weight regain in the AT group.

FTO-associated obesity risk is linked to altered brain function at rest and in response to food (8, 9