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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2020 Oct 19;106(4):1837–1848. doi: 10.1210/clinem/dgaa746

The Effects of Kisspeptin on Brain Response to Food Images and Psychometric Parameters of Appetite in Healthy Men

Lisa Yang 1,2, Lysia Demetriou 2,2, Matthew B Wall 2, Edouard G Mills 1, Victoria C Wing 1, Layla Thurston 1, Caroline N Schaufelberger 2, Bryn M Owen 1, Ali Abbara 1, Eugenii A Rabiner 2, Alexander N Comninos 1,3,✉,✉, Waljit S Dhillo 1,3,✉,✉
PMCID: PMC7993584  PMID: 33075807

Abstract

Context

The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans.

Objective

This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men.

Design

A double-blinded, randomized, placebo-controlled, crossover study was conducted.

Participants

Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2).

Intervention

Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes.

Main Outcome Measures

Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle.

Results

Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle.

Conclusions

This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism.

Keywords: kisspeptin, appetite, fMRI, food, reward, behavior

Reproduction and metabolism are intricately linked processes that are essential for survival. Disturbances in reproductive function or metabolic energy balance can have reciprocal detrimental effects on each other (1, 2), yet our understanding of the key hormonal links between reproduction and metabolism remains limited. Furthering our knowledge of these links has major clinical significance given the growing worldwide prevalence of obesity and its consequent detrimental effects on reproduction and fertility (3, 4).

The hormone kisspeptin sits at the apex of the reproductive axis, where it has a crucial role in controlling downstream hormone release (5, 6). In addition to its well-characterized role in reproduction (7-9), emerging neuroanatomical and functional data suggest that kisspeptin has important metabolic functions (10-12). These include effects on appetite and feeding behaviors, as evidenced by altered food intake accompanied by metabolic derangements in mice with disrupted kisspeptin signaling (13, 14). It is therefore imperative to understand how kisspeptin mediates its effects on appetite and feeding behaviors. However, data in this area remain limited to animal models (15, 16) and thus far there have been no human studies exploring kisspeptin’s effects on neural and behavioral responses to food stimuli.

Kisspeptin and its receptor have been localized to numerous limbic brain areas in humans (17, 18) including the amygdala, anterior cingulate cortex (ACC), caudate, hippocampus, orbitofrontal cortex (OFC), putamen, and thalamus, which are all involved in the regulation of appetite and food reward (19). Therefore, examining the effects of kisspeptin administration on brain responses to visual food stimuli could provide key translational insights into the interactions between kisspeptin and appetite in humans. In this study we used functional magnetic resonance imaging (fMRI) and psychometric and hormonal analyses to investigate the effects of kisspeptin on brain responses to visual food stimuli and psychometric appetite parameters in healthy men.

Materials and Methods

Participants

This study was performed in accordance with the Declaration of Helsinki. All participants gave written informed consent prior to inclusion in the study. The study was approved by the Riverside Research Ethics Committee, London, UK (REC ref: 17/LO/1504).

Following recruitment using online and print advertisements, interested individuals were invited to screening. All men underwent detailed medical history and clinical examination (including endocrine and neurological assessment). Blood tests, including the following, were assessed during the screening visit to confirm health status and exclude an endocrine abnormality: full blood count, renal function, liver function, bone profile, thyroid hormone profile, luteinizing hormone (LH), follicle-stimulating hormone, testosterone, sex hormone binding-globulin, and nonfasted glucose measurement. All participants had structurally normal brains on MRI as reported by a neuroradiologist.

Following screening and informed consent, 31 men took part in the study. Two participants did not complete both study visits and 2 men were excluded, resulting in a final study group of 27 healthy, right-handed men (mean age 26.5 ± 1.1 years; mean body mass index 23.9 ± 0.4 kg/m2). This sample size was selected to give sufficient power to detect a difference in fMRI activity following a hormonal intervention compared with vehicle, which compares favorably with other fMRI studies (20) and our previous work (21, 22). It is also in line with empirically derived estimates of optimal sample sizes in fMRI studies, which suggest that 20 to 24 participants is the minimal number required to give sufficient power to detect moderate-sized effects (23).

Individuals were excluded based on the following criteria: body mass index less than 18.5 or greater than 25 kg/m2; history of medical or psychological conditions; use of prescription, recreational, or investigational drugs within the preceding 2 months; blood donation within 3 months of study participation; abnormal eating behavior; or history of cancer.

Study design

Each participant attended 2 study visits, one for administration of kisspeptin and one for administration of vehicle (Fig. 1). The order of the infusions was randomized (using www.randomizer.org) and participants were blinded to the identity of the infusions. This was a within-participant design study, in which the participants acted as their own control thereby minimizing variability and enhancing power. All study visits commenced in the morning to control for circadian hormonal changes. Participants were instructed to refrain from strenuous activity from 20:00, and abstain from alcohol, caffeine and fast from 22:00 the night preceding each study visit. On arrival, participants were asked to remove any metal on their person and change into loose hospital scrubs. After a period of acclimatization, 2 intravenous cannulae (one in each arm) were inserted (one cannula was used for blood sampling and the second for administering the infusion). Blood sampling took place at 15 minute intervals from –30 to 75 minutes to measure circulating LH and testosterone levels. At T = 0 minutes, a 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) or vehicle (gelofusine at equivalent rate) was given. This kisspeptin dose was selected based on our previous experience (21, 24), to ensure steady-state levels of circulating kisspeptin from 30 to 75 minutes (during the fMRI task), while avoiding any increase in downstream testosterone, which has previously been shown to occur following longer periods of kisspeptin exposure in humans (25). Participants completed psychometric questionnaires before and toward the end of the kisspeptin or vehicle infusion as detailed later. The fMRI task was initiated at 30 minutes from the start of the infusion to allow circulating kisspeptin levels to reach steady state as per our previous work (21, 24).

Figure 1.

Figure 1.

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Study protocol. Twenty-seven healthy men participated in a randomized, double-blind, 2-way crossover, placebo-controlled study. They attended 2 study visits: one for intravenous administration of kisspeptin (1 nmol/kg/h) and one for intravenous administration of an equivalent volume of vehicle for 75 minutes. Blood samples were taken every 15 minutes (x). Participants completed baseline and intrainfusion psychometric questionnaires (Q) and underwent functional magnetic resonance imaging (fMRI) scanning while performing a visual food task.

Biochemical analyses

Serum LH and testosterone were measured using automated chemiluminescent immunoassays (Abbott Diagnostics). The intra-assay and interassay coefficients of variation were less than 5% for LH and testosterone. Analytical sensitivities were 0.5 IU/L (LH) and 2 nmol/L (testosterone). Limits of detectability for each assay were 0.07 IU/L (LH) and 4.9 nmol/L (testosterone).

Functional magnetic resonance imaging procedure

During the MRI session, a series of anatomical and functional brain scans were performed. During the food image task, a mirror mounted on the head coil was used to view a screen at the rear of the scanner bore, onto which the stimuli were projected. To respond to the task, the participants were equipped with a custom-made, 5-button, MRI-compatible response box. Kisspeptin and vehicle infusions were administered via a Medrad Spectris Solaris MRI-compatible injection system controlled from a remote panel in the control room.

Visual food task

In keeping with previously validated protocols, participants were presented with images of high-calorie foods, low-calorie foods, and nonfood images (control) displayed on identical backgrounds (22, 26). All images were selected from a database of standardized color photographs of food and nonfood images that have been validated across several European countries by independent adult raters (27). Both the high- and low-calorie food images comprised sweet and savory food items. Nonfood items included stationery, such as staples, pencils, paper clips, elastic bands, and post-it notes. Food and nonfood items were presented on a white plate to ensure a consistent visual appearance and a light gray background to ensure an adequate contrast between the plate and background (27). All images are freely available online (http://nutritionalneuroscience.eu/).

High-calorie food, low-calorie food, and nonfood images were presented sequentially in blocks of 4 images. Resting blocks, in which a gray screen with a central fixation cross was displayed, were also included to provide a baseline. Each image was displayed for 4 seconds, with 8 blocks of each type (high-calorie food, low-calorie food, nonfood, and resting blocks), and 32 blocks in total. Blocks were presented in a predetermined pseudo-random order in which the order of blocks was randomized within meta-blocks of 4 (1 of each type), and with the constraint that the same block type could not be presented successively (ie, at the end of one meta-block, and the beginning of the next). To maintain alertness and task engagement, participants were asked to rate the pleasantness of each image on a 5-point scale ranging from “very unpleasant” to “very pleasant” using the 5-button MRI-compatible response box.

Magnetic resonance imaging acquisition

Imaging data were acquired using a 3T Siemens Trio scanner with a 32-channel, phased-array head coil. Anatomical images were acquired at the beginning of each scan using a T1-weighted magnetization prepared rapid gradient echo pulse sequence (1 mm isotropic voxels, repetition time [TR] = 2300 ms, echo time [TE] = 2.98 ms, flip angle = 9°). For the acquisition of functional images during the food task, a multiband sequence with acceleration factor 2 was used with the following parameters: 3 mm voxels, TR = 1250 ms, TE = 30 ms, flip angle = 80°, and 44 axial slices.

Functional magnetic resonance imaging data analysis

Imaging analysis was performed using FSL. Preprocessing included motion correction, smoothing (6 mm), registration to a standard template (MNI152), and high-pass filtering (0.01 Hz). A general linear model analysis modeled the occurrence of the stimuli and included their temporal derivatives and extended head-motion regressors as confounds. Group analyses were random-effects (FLAME-1) models, with statistical maps thresholded at z = 3.1 and P less than .05 (cluster-corrected).

A set of a priori–selected brain regions defined in standard stereotactic space using the Harvard-Oxford atlases (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/) was used to extract data for region of interest (ROI) analyses. Regions were selected to include limbic brain areas involved in appetite and food-reward pathways that also express kisspeptin receptors in humans. These comprised the amygdala, ACC, caudate, globus pallidus, hippocampus, insula, nucleus accumbens, putamen, OFC, and thalamus (22, 26, 28-30). Additionally, a composite “food-reward” mask was derived by using meta-analytic data associated with the search term “food” within the Neurosynth database (http://neurosynth.org/) to assess system-based effects of kisspeptin compared to vehicle during the food task. The “food-reward” mask incorporated the hypothalamus in addition to other important brain regions involved in appetite. However, the hypothalamus was not included as part of the a priori set of individual ROIs because of its small size and susceptibility to signal loss from the air-tissue interface of adjacent sinuses, which limits its reliability as a robust ROI (31, 32).

Main outcome measures

The primary outcome measure was change in brain activity as measured by fMRI blood oxygen level–dependent (BOLD) activity in response to food images during kisspeptin compared to vehicle administration. Secondary outcomes included changes in psychometric parameters of appetite and changes in downstream circulating LH and testosterone levels.

Statistical methods

Statistical analyses were performed using GraphPad Prism 8 and Jamovi statistical software. Data were normally distributed by Kolmogorov testing. Hormone level data were analyzed using a mixed-model analysis of variance. Paired 2-tailed t tests were performed to investigate the effects of kisspeptin compared to vehicle on each individual ROI, with an α threshold of P less than .05 determining statistical significance as used previously (21, 24).

Psychometric questionnaires

At their first study visit, participants were asked to complete a set of psychometric questionnaires to assess certain baseline traits prior to commencing the infusion and starting the MRI scan. The State-Trait Anxiety Inventory (33) was used to record longstanding trait anxiety levels. The Three-Factor Eating Questionnaire was used to collect data on eating traits including cognitive restraint, uncontrolled eating, and emotional eating (34). Behavioral Inhibition and Activation System Scales (BIS/BAS) (35) were used to assess tendency toward anticipation of punishment (BIS) and to reward (BAS), traits that have been shown to predict fMRI brain responses to appetizing food images (26).

A second set of questionnaires was used to assess appetite and satiety parameters in the current moment. A 10-cm visual analog scale (VAS) recorded responses to 6 questions assessing hunger, satiety, nausea, and sleepiness. The Food Cravings Questionnaire (FCQ), validated for the assessment of hunger in the general population and in appetite studies (36-38), explored food cravings using 5 domains: an intense desire to eat, anticipation of positive reinforcement that may result from eating, anticipation of relief from negative states as a result of eating, a lack of control over eating, and hunger as a physiological state. Each participant was asked to complete these questionnaires before and toward the end of the infusion (kisspeptin or vehicle) on his first and second study visits.

Results

Effects of kisspeptin administration on circulating hormone levels

Intravenous kisspeptin administration (1 nmol/kg/h) significantly increased serum LH to similar levels described previously using this administration protocol (21, 24), which confirmed that the dose of kisspeptin used was biologically active (Fig. 2A). As expected, kisspeptin administration had no significant effects on testosterone levels during the 75-minute study period (Fig. 2B), in keeping with our previous work (21, 24).

Figure 2.

Figure 2.

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Effects of peripheral kisspeptin administration on circulating hormone levels. A, Kisspeptin infusion significantly increased circulating levels of luteinizing hormone (LH) compared to vehicle. B, Kisspeptin had no effect on circulating testosterone levels in this timeframe. Data depict mean ± SEM. ****P less than .0001 using mixed-model analysis of variance (N = 27).

Effects of kisspeptin administration on brain responses to food images

Whole-brain voxel-wise analysis.

Group-mean analysis of the food image trials for all participants in both their kisspeptin and vehicle study visits showed increased activity in key brain regions involved in appetite and food-reward processing. This demonstrated that the food images (high-calorie, low-calorie, and all food) robustly stimulated fMRI BOLD activity in key brain regions more than the nonfood images as expected, thus confirming the effectiveness of the task (Fig. 3A).

Figure 3.

Figure 3.

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Task means and treatment effects for food and nonfood images. A, Group mean analysis results for the main effects of the food image trials in all participants and both treatments (kisspeptin and vehicle) showing increase in blood oxygen level–dependent (BOLD) activity for food greater than nonfood images, high-calorie food greater than nonfood images, and low-calorie food greater than nonfood images (N = 27). B, Within-subject whole-brain analysis of the effects of kisspeptin (KP) vs vehicle (VH) administration for food greater than nonfood images, high-calorie food greater than nonfood images, and low-calorie food greater than nonfood images showing no effects on BOLD activity for KP greater than VH or KP less than VH (N = 27). Positive voxel values (red-yellow) represent an increase in BOLD activity. All statistical maps thresholded at z = 3.1, P less than .05 (cluster-corrected for multiple comparisons).

Subsequently, a treatment comparison analysis was carried out on a whole-brain voxel-wise level to compare differences in brain response between the kisspeptin and vehicle visits. This showed no differences in brain activity during kisspeptin compared to vehicle administration in all brain areas including the hypothalamus and limbic regions, for food images (high-calorie, low-calorie, and all food) compared to nonfood images (Fig. 3B).

Region of interest analysis.

To further assess the effects of kisspeptin compared to vehicle on BOLD activity during the food task, ROI analyses were performed on a priori–defined anatomical regions: amygdala, ACC, caudate, globus pallidus, hippocampus, insula, nucleus accumbens, OFC, putamen, and thalamus. The results showed no significant differences between kisspeptin and vehicle administration for food images (high-calorie, low-calorie, and all food) compared to nonfood images in any of the ROIs that were assessed (Table 1). Additionally, a systems-based ROI analysis was employed using a “food-reward” brain mask derived from meta-analytic data within the Neurosynth database (39). This also showed no significant differences between kisspeptin and vehicle administration in the food-reward system when viewing food images compared to nonfood images (see Table 1 and Supplementary Figure 1 [40] http://doi.org/10.14469/hpc/7431).

Table 1.

Region of interest analysis of kisspeptin vs vehicle effects during food task

Kisspeptin Vehicle Statistic df P
All food—non-food
Accumbens Accumbens 0.339 26.0 .737
Amygdala Amygdala –0.220 26.0 .828
ACC ACC –0.888 26.0 .383
Caudate Caudate 0.189 26.0 .852
Globus pallidus Globus pallidus 0.066 26.0 .948
Hippocampus Hippocampus 0.031 26.0 .976
Insula Insula –0.122 26.0 .904
OFC OFC –0.232 26.0 .818
Putamen Putamen 0.001 26.0 1.000
Thalamus Thalamus 0.953 26.0 .349
“Food reward” mask “Food reward” mask –0.317 26.0 .754
High-calorie food—non-food
Accumbens Accumbens 0.073 26.0 .943
Amygdala Amygdala –0.220 26.0 .828
ACC AC –0.062 26.0 .951
Caudate Caudate –0.547 26.0 .589
Globus pallidus Globus pallidus 0.022 26.0 .982
Hippocampus Hippocampus –0.577 26.0 .569
Insula Insula –0.045 26.0 .964
OFC OFC –0.287 26.0 .776
Putamen Putamen 0.450 26.0 .656
Thalamus Thalamus –0.212 26.0 .834
“Food reward” mask “Food reward” mask –0.186 26.0 .855
Low-calorie food—non-food
Accumbens Accumbens 0.626 26.0 .537
Amygdala Amygdala –0.526 26.0 .603
ACC ACC 0.483 26.0 .633
Caudate Caudate –0.111 26.0 .913
Globus pallidus Globus pallidus 0.321 26.0 .751
Hippocampus Hippocampus –0.002 26.0 .999
Insula Insula 0.022 26.0 .982
OFC OFC 0.646 26.0 .524
Putamen Putamen 0.271 26.0 .789
Thalamus Thalamus 0.028 26.0 .978
“Food reward” mask “Food reward” mask 0.027 26.0 .979
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Effects of kisspeptin compared to vehicle on percentage blood oxygen level–dependent (% BOLD) signal change in a priori anatomical regions of interest. No significant differences in % BOLD activity between kisspeptin and vehicle. Paired 2-tailed t tests (N = 27).

Abbreviations: ACC, anterior cingulate cortex; df, degree of freedom; OFC, orbitofrontal cortex.

Participant ratings of food and nonfood images.

During the fMRI task, participants were asked to rate each image according to their subjective pleasantness on a scale of 1 to 5 (1 = very unpleasant, 5 = very pleasant). Participants rated food images (high-calorie and low-calorie) as more pleasant than the nonfood images as expected; however, there were no significant differences in perceived pleasantness of images between kisspeptin and vehicle administration (Supplementary Table 1 [40] http://doi.org/10.14469/hpc/7431).

Effects of kisspeptin administration on psychometric parameters of appetite

Baseline appetite scores as measured by VAS and FCQ were equivalent across all domains on both study visits (see Supplementary Table 1 (40) http://doi.org/10.14469/hpc/7431), and there were no significant differences in other potential confounding factors such as nausea (t(26) = 0.588, P = .561) or sleepiness (t(26) = 0.215, P = .831) during kisspeptin administration compared to vehicle (Fig. 4). In addition, there were no significant changes in psychometric parameters of appetite as measured by VAS and FCQ during kisspeptin administration compared to vehicle (Figs. 4 and 5).

Figure 4.

Figure 4.

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Change in visual analog scale (VAS) parameters during kisspeptin and vehicle administration. How hungry are you right now: t(26) = 0.078, P = .938; How full do you feel right now: t(26) = 0.294, P = .771; How pleasant would it be to eat right now: t(26) = 0.533, P = .599; How much could you eat right now: t(26) = 0.358, P = .724; How nauseous do you feel right now: t(26) = 0.588, P = .561; How sleepy do you feel right now: t(26) = 0.215, P = .831). Data presented as within-participant paired raw data and box and whiskers plot depicting maximum, minimum, and mean values. Paired 2-tailed t tests (N = 27).

Figure 5.

Figure 5.

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Change in Food Cravings Questionnaire (FCQ) parameters during kisspeptin and vehicle administration. Intense desire to eat: t(26) = 0.553, P = .585; Hunger as a physiological state: t(26) = 0.631, P = .534; Anticipation of positive reinforcement; t(26) = 0, P > .999; Anticipation of relief from negative states: t(26) = 0.147, P = .884; Lack of control over eating: t(26) = 0.589, P = .561; Total score: t(26) = 0.599, P = .554. Data presented as within-participant paired raw data and box and whiskers plot depicting maximum, minimum, and mean values. Paired 2-tailed t tests (N = 27).

Discussion

This is the first fMRI study to investigate the effects of kisspeptin on brain regions regulating appetite and food-reward in humans. Our results demonstrate that peripheral kisspeptin administered as an intravenous infusion does not affect brain processing in response to visual food stimuli in healthy men. Consistent with this, kisspeptin administration does not have any significant effects on psychometric parameters of appetite.

Our previous human fMRI studies have shown that peripheral kisspeptin administration enhances brain-reward pathways in response to sexual and couple-bonding images (21), and to olfactory and visual cues of attraction (24). Food images can be considered another form of rewarding stimuli in humans. However, despite clear and robust task effects of food compared to nonfood images similar to published protocols (22, 26), kisspeptin did not elicit significant changes in brain responses to visual food stimuli in this study. This suggests that kisspeptin’s effects on limbic brain regions are more specific to sexual stimuli and attraction cues in healthy men.

In this study, an intravenous kisspeptin-54 infusion was administered at a dose known to be bioactive in healthy men as confirmed by an increase in serum LH, which is in keeping with our previous work using similar administration protocols (21, 24). Moreover, peripherally administered kisspeptin-54 is capable of penetrating the blood-brain barrier to reach deeper brain structures known to express kisspeptin and its receptor (21, 41). Thus, methodologically, the route and dose of kisspeptin administration used in this study were sufficient to access brain regions involved in appetite and food-reward processing in humans.

We also took precautions to reduce sources of variability, and control for potential confounders by recruiting healthy eugonadal men of similar age, with normal baseline eating behaviors. All participants followed the same instructions regarding food, strenuous activity, alcohol, and caffeine intake prior to each study visit. Study visits were performed in a randomized order with participants blinded to the contents of the intravenous infusions. Additionally, all studies commenced in the morning to ensure peak basal reproductive hormone levels, and fMRI tasks were completed prior to any downstream increases in circulating testosterone.

Although there are some reports that kisspeptin administered both centrally and peripherally can reduce food intake in rodents (42-44), other data suggest that central and peripheral administration of kisspeptin has no effect on food intake in male rats in acute or chronic settings (45-47). In keeping with this, a recent human study demonstrated no differences in ad libitum food intake during a peripheral kisspeptin administration compared to vehicle (48). The results presented in this present human study suggest there is no significant effect of kisspeptin on brain responses to visual food stimuli or psychometric appetite parameters in healthy men and thereby answers key questions relating to the role of kisspeptin in human appetite.

In addition to visual stimulation, food odors are also involved in brain-reward responses to food. However, although olfaction is important in determining the palatability of food, vision is generally regarded as more important for food-seeking in humans (49). Moreover, while previous fMRI studies demonstrate that food odors are able to modulate brain-reward circuits (50-52), these studies are somewhat limited by their investigation of pleasant odors only. In our study, we assessed food reward purely using visual food stimuli as cues. Given the established participation of kisspeptin-signaling both in rodent (53, 54) and human (24) reproductive olfactory processes, the effect of kisspeptin on food-related olfactory processes may be an interesting area of future investigation.

It is important to note that our findings are limited to healthy eugonadal men. In animal studies, female Kiss1r knockout mice display different bodyweight changes and metabolic derangements compared to Kiss1r knockout male mice (13, 14). Hence future fMRI studies to investigate the effects of kisspeptin on brain response to food stimuli in women are imperative, as well as in patients with reproductive and/or metabolic disorders. Indeed, it would be useful to assess the effects of kisspeptin on appetite and food reward in patients with hypothalamic amenorrhea because this condition is associated with derangements in nutritional intake and energy balance (55), which is underpinned by abnormal hypothalamic-pituitary signaling that can be ameliorated by kisspeptin administration (8). Additionally, emerging animal data suggest that the effects of kisspeptin on metabolism may be driven primarily through modulation of energy expenditure rather than food intake (13, 56, 57). Our data support this concept in humans, and future studies investigating the effects of kisspeptin administration on energy expenditure in humans would thus be highly relevant.

In summary, this is the first study to examine the effects of kisspeptin on brain responses to visual food stimuli and psychometric parameters of appetite in humans. These data provide important translational insights to further our understanding of the interaction between reproduction and metabolism in humans.

Acknowledgments

Financial Support: This work was supported by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre and NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the MRC, the NIHR, or the Department of Health. L.Y. and E.G.M. are funded by Medical Research Council Clinical Research Training Fellowships (MR/R000484/1 and MR/T006242/1); V.W. is supported by the National Institute for Health Research Academic Foundation Programme; B.M.O. is supported by a Sir Henry Dale Fellowship (105545/Z/14/Z) jointly funded by the Wellcome Trust and the Royal Society; A.A. is funded by an National Institute for Health Clinician Scientist Fellowship (CS-2018-18-ST2-002); A.N.C. is funded by the UK National Health Service; and W.S.D. is funded by an National Institute for Health Research Professorship (NIHR RP-2014-05-001).

Glossary

Abbreviations

ACC

anterior cingulate cortex

BIS/BAS

Behavioral Inhibition and Activation System Scales

BOLD

blood oxygen level–dependent

FCQ

Food Cravings Questionnaire

fMRI

functional magnetic resonance imaging

LH

luteinizing hormone

OFC

orbitofrontal cortex

ROI

region of interest

VAS

visual analog scale.

Additional Information

Disclosure Summary: A.A. and W.S.D. have undertaken consultancy work for Myovant Sciences Ltd. W.S.D. has undertaken consultancy work for KaNDy Therapeutics. The other authors have nothing to disclose.

Data Availability

Some or all data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.

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