Introduction and Objective: Brain insulin sensitivity plays a central role in coordinating whole-body metabolism. In humans, reduced brain insulin responsiveness is linked to weight gain, visceral adiposity, and impaired metabolic control. Experimental work shows that intranasal insulin (INI) delivers insulin to the brain with minimal systemic effects. Building on this concept, we aimed to enhance central insulin signaling in humans through long-term INI treatment. We hypothesized that INI treatment enhances brain insulin sensitivity while leading to a more favorable body fat distribution. Methods: In this randomized, controlled, blinded study, 39 healthy individuals (age 60.6 ± 7.4 years; 67% women) were randomized to daily INI (160 IU, n=19) or placebo (PLA, n=20) spray treatment for 8 weeks. Before (t=0) and after (t=8wk) the treatment period, individuals were deeply phenotyped, including whole-body MRI for body fat quantification and functional MRI combined with acute INI to assess brain insulin sensitivity. Data are displayed as median ± 95% CI. Results: Body mass index (BMI) was similar between groups at baseline (t=0, INI: 28.2 ± 2.3 vs PLA 29.7 ± 3.1 kg/m2; p=0.51) and decreased only in the INI group (t=8wk, BMI: INI 27.3 ± 2.3, vs t=0; p=0.046, PLA: 30.2 ± 3.0 kg/m2, vs t=0; p=0.14). This was paralleled by a reduction in subcutaneous adipose tissue in the INI but not in the PLA group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI 13.3 ± 2.2 L vs 12.5 ± 2.3 L; p=0.03; PLA 14.0 ± 2.7 L vs 15.4 ± 3.0 L; p=0.93). Hypothalamic insulin sensitivity increased in the INI but not in the placebo group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI p=0.007; PLA p>0.99). Conclusion: Chronic INI treatment improves hypothalamic insulin sensitivity in adults with overweight or obesity, and this effect is accompanied by a reduction in BMI and subcutaneous fat. These findings highlight brain insulin responsiveness as a therapeutic target to counteract elevated body weight and body fat content. Disclosure L. Sandforth: None. R. Veit: None. C. Dannecker: None. R.J. von Schwartzenberg: None. A. Vosseler: None. M. Hallschmid: None. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk. A.L. Birkenfeld: None. P. Hubert: None. A. Fritsche: None. M. Heni: Advisory Panel; Ended; Chiesi USA, Inc. Speaker's Bureau; Ended; Chiesi USA, Inc. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH, AstraZeneca, Lilly, Novartis AG, Novo Nordisk, Bayer AG. S. Kullmann: None.

Impairments in peripheral glucose metabolism and reduced brain insulin sensitivity are linked to an increased risk of both metabolic and neurodegenerative diseases. Brain insulin resistance represents a shared pathological mechanism underlying these disorders. Notably, hippocampal insulin responsiveness declines with age and differs between men and women. This study aimed to identify clinically relevant metabolic predictors of hippocampal insulin sensitivity in the context of age and sex. In 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m2, mean age 44.2 ± 16.6 years), functional MRI was performed before and after intranasal insulin administration to assess hippocampal insulin response. Metabolic phenotyping comprised laboratory assessments including oral glucose tolerance tests, whole-body MRI and 1H-MRS. In addition, participants were assigned to high- and low-risk prediabetes clusters using the Tübingen risk cluster tool. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance and/or elevated HbA1c. We used linear regression models to select the most relevant predictors, including interactions with sex and age. Fasting plasma glucose levels predicted lower hippocampal insulin response with age independently of sex (estimate 0.533, p=0.016). Significant interactions were present between age, sex and body fat distribution (waist-to-hip ratio [WHR]: estimate 0.233, p=0.010; visceral adipose tissue [VAT]: estimate 0.007, p=0.013; intrahepatic lipid content [IHL]: estimate 0.003, p=0.010). In women, higher WHR, VAT and IHL were predictors of lower hippocampal insulin responsiveness with increasing age. These effects remained significant after adjusting for BMI. Postmenopausal women showed lower hippocampal insulin responsiveness with higher WHR and IHL (p<0.05), and women in high-risk Tübingen prediabetes clusters also showed lower hippocampal insulin responsiveness than men (sex × cluster type: estimate 0.39, p=0.02). The hippocampal insulin response did not correlate with hippocampal volume (p>0.05). Unhealthy body fat distribution was a sex-dependent predictor for decreased hippocampal insulin sensitivity with increasing age. Older women with high abdominal fat and/or those assigned to high-risk clusters were most vulnerable to impaired insulin responsiveness in the hippocampus. These findings may contribute to explaining sex differences in the development of type 2 diabetes and neurodegenerative diseases.

The menstrual cycle impacts food intake, peripheral metabolism, and brain function. One well-known central regulator of eating behavior is the hormone insulin. Here, we show that the responsiveness of functional brain networks to central insulin varies dynamically across the menstrual cycle in premenopausal women. Intranasal insulin (INI) administration increases functional connectivity within networks that support decision-making processes (namely the default mode and salience network) in the follicular compared to the luteal phase of the menstrual cycle. In contrast, INI decreases functional connectivity within the somatosensory network during the follicular phase relative to the luteal phase. In response to visual food cues, hippocampus and dorsal striatum activity are higher in the luteal compared to the follicular phase, particularly to sweet food. Estradiol and progesterone levels predict these changes. This could contribute to higher food craving and food intake observed in the luteal phase. Our findings emphasize sex hormones' role in modulating brain sensitivity to hormonal signals and external stimuli.

AIMS:Elevated fasting glucagon is linked to hyperglycemia, but postprandial glucagon effects are less understood. Recent evidence suggests metabolic benefits of rising glucagon after oral glucose intake, potentially impacting brain-mediated whole-body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. MATERIALS AND METHODS:We performed oral glucose tolerance tests (OGTT) combined with functional magnetic resonance imaging to quantify brain activity and connectivity at fasting, 30 and 120 min post glucose load in 30 volunteers. In 14 participants with suppressed glucagon, low-dose glucagon infusion mimicked non-suppressed glucagon after OGTT. This was compared to 7 participants with endogenous rising glucagon during OGTT. RESULTS:Low-dose glucagon infusion did not elevate plasma glucose levels during OGTT. Also, no changes in insulin sensitivity and insulin secretion were observed. However, experimentally elevating glucagon during OGTT in individuals with physiological suppression of glucagon significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the homeostatic and hedonic regulation of food intake as well as systemic metabolism (i.e., hypothalamus and ventral striatum). Most postprandial brain responsiveness during glucagon infusion was directionally consistent with the findings in persons with endogenously rising glucagon. Moreover, the postprandial brain response correlated with the rise in glucagon, regardless of exogenous or endogenous source of glucagon. Although the overall glucagon trajectory during OGTT was not significantly different over the full 0-150 min period, the groups differed at key post-challenge timepoints and in integrated glucagon exposure. Together with the infusion and correlation analyses, this supports a relationship between postprandial glucagon and brain responsivity, while more subtle differences in glucagon kinetics will require larger studies. CONCLUSIONS:Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underlie the promising effects on body weight achieved with pharmacological multi-agonists that activate the glucagon receptor.

Background Drinks with low-no-calorie sweeteners (LNCSs) do not contribute to energy intake but still provide a hedonic experience through sweetness. LNCS can have differential effects on brain areas involved in food intake and reward compared with sugars. Objectives This study determined changes in brain activity and the effect on physiological markers following the ingestion of flavored waters sweetened with the sugar sucrose or LNCS. Methods Thirty healthy individuals participated in a randomized crossover study with 6 treatments. Participants were scanned after an overnight fast using magnetic resonance imaging, including arterial spin labeling to measure cerebral blood flow (CBF), before and after ingestion of 500-mL drinks: water, or equisweet flavored waters with 25 g sucrose, sucralose, stevia extract, allulose+stevia extract, or monk fruit extract. CBF was measured at baseline and 5 and 30 min; gastric content volume was measured at baseline and 25 and 45 min. Serum insulin and glucose were measured, and participants rated their appetite and thirst throughout each visit. Data were analyzed with linear mixed models. Results Primary: Hypothalamus CBF was not differentially affected by any of the drinks. In the ventral tegmental area (midbrain), treatment effects differed, with lower ΔCBF after sucrose than water, sucralose and monk fruit drink ingestion at 30 min (difference: ∼8% ± 3%; all PFDR < 0.05). Exploratory whole-brain analyses showed increased CBF after consumption for allulose+stevia (amygdala) and stevia (putamen) compared with sucrose (PFWE < 0.05). Despite its low energy content, allulose+stevia delayed gastric emptying similar to sucrose, whereas only sucrose increased glucose and insulin concentrations. Conclusions Although flavored waters with LNCS mostly elicit similar neural and gastrointestinal responses as water, they have some distinct effects on the brain compared with 25 g of sucrose, particularly in reward-related brain areas. Further exploration of the neural and physiological effects of allulose and stevia and dose-dependent investigations are warranted.This study was registered at clinicaltrials.gov as NCT05575687 (https://clinicaltrials.gov/study/NCT05575687).

Sucralose, a widely used non-caloric sweetener, provides sweet taste without calories. Some studies suggest that non-caloric sweeteners stimulate appetite, possibly owing to the delivery of a sweet taste without the post-ingestive metabolic signals that normally communicate with the hypothalamus to suppress hunger. In a randomized crossover trial (ClinicalTrials.gov identifier: NCT02945475 ), 75 young adults (healthy weight, overweight or with obesity) consumed a drink containing sucralose, sweetness-matched sucrose or water. We show that acute consumption of sucralose versus sucrose stimulates hypothalamic blood flow (P < 0.018) and greater hunger responses (P < 0.001). Sucralose versus water also increases hypothalamic blood flow (P < 0.019) but produces no difference in hunger ratings. Sucrose, but not sucralose, increases peripheral glucose levels, which are associated with reductions in medial hypothalamic blood flow (P < 0.007). Sucralose, compared to sucrose and water, results in increased functional connections between the hypothalamus and brain regions involved in motivation and somatosensory processing. These findings suggest that non-caloric sweeteners could affect key mechanisms in the hypothalamus responsible for appetite regulation. In a randomized, crossover clinical trial in healthy young adults with varying weights, sucralose increased hypothalamic blood flow and its functional connections with brain regions involved in motivation and somatosensory processing.

BACKGROUND:Reduced inhibitory control is associated with obesity and neuroimaging studies indicate that diminished prefrontal cortex activity influence eating behavior and metabolism. The hypothalamus regulates energy homeostasis and is functionally connected to cortical and subcortical regions especially the frontal areas. OBJECTIVES:We tested network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in appetite control. METHODS:In a randomized, double-blind parallel group design, 44 adults with overweight or obesity (BMI 30.6 kg/m2, 52.3 % female) received active (anodal or cathodal) or sham 12-channel net-tDCS on the hypothalamus appetite-control network for 25 min on three consecutive days while performing a Stop-Signal-Task to measure response inhibition. Before and after stimulation, state questionnaires assessed changes in desire to eat and food craving. Directly after stimulation, participants received a breakfast buffet to evaluate ad-libitum food intake. An oral glucose tolerance test was conducted at follow-up. Resting-state functional MRI was obtained at baseline and follow-up. RESULTS:The Stop-Signal Reaction Time (SSRT) was shorter in both active groups versus sham, indicating improved response inhibition. Additionally, a stronger increase in hypothalamic functional connectivity was associated with shorter SSRT. Caloric intake of sweet food was lower in the anodal group versus sham, but no main effects between groups were observed on total and macronutrient intake, food craving ratings and desire to eat. At follow-up, no differences were observed between groups on peripheral metabolism. CONCLUSION:Our study suggests that modulating hypothalamic functional network connectivity patterns via net-tDCS may improve food choice and inhibitory control.

OBJECTIVE:Insulin resistance during childhood is a risk factor for developing type 2 diabetes and other health problems later in life. Studies in adults have shown that insulin resistance affects regional and network activity in the brain which are vital for behavior, including ingestion and metabolic control. To date, no study has investigated how brain connections during exposure to food cues are association with peripheral insulin sensitivity in children. METHODS:We included 53 children (36 girls) between the age of 7-11 years, who underwent an oral Glucose Tolerance Test (oGTT) to estimate peripheral insulin sensitivity (ISI). Brain responses were measured using functional magnetic resonance imaging (fMRI) before and after glucose ingestion. We compared food-cue task-based activity and functional connectivity (FC) between children with lower and higher ISI, adjusted for age and BMIz. RESULTS:Independent of prandial state (i.e., glucose ingestion), children with lower ISI showed higher FC between the anterior insula and caudate and lower FC between the posterior insula and mid temporal cortex than children with higher ISI. Sex differences were found based on prandial state and peripheral insulin sensitivity in the insular FC. No differences were found on mean brain responses to food cues. CONCLUSIONS:In response to food cues, children with lower peripheral insulin sensitivity exhibited distinctive patterns of neural connectivity, notably in the insula's functional connections, when contrasted with their counterparts with higher peripheral insulin sensitivity. These differences might influence eating behavior and future risk of developing diabetes.

Obesity, particularly pediatric obesity, has dramatically increased over the last three decades, with a wide range of detrimental health outcomes, including negative consequences for brain neurodevelopment. The present article reviewed magnetic resonance imaging studies between January 2011 and March 2024 examining the brain's role in pediatric obesity, including parental influences and diverse interventions. A literature search identified 97 eligible MRI studies in the pediatric population. Findings suggest that altered brain structures and functions in pediatric obesity are strongly dependent on the developmental stage of children and adolescents. The function and structure of limbic regions, such as the hippocampus, amygdala, and striatum, as well as the prefrontal cortex, seem to be particularly affected by higher body mass index during development. In response to palatable foods, children and adolescents with excess weight have increased activation in reward-related regions and decreased activation in regions involved in interoceptive signal processing, especially during decision processes. In addition, children of mothers with obesity and gestational diabetes mellitus show alterations in brain structure and function independent of their current obesity. Behavioral, exercise, and weight-loss intervention studies showed promising effects on the brain, with increased structural integrity, decreased brain responses to reward, and strengthened inhibitory brain responses in children and adolescents with excess weight after the intervention.

Brain insulin responsiveness is linked to long-term weight gain and unhealthy body fat distribution. Here we show that short-term overeating with calorie-rich sweet and fatty foods triggers liver fat accumulation and disrupted brain insulin action that outlasted the time-frame of its consumption in healthy weight men. Hence, brain response to insulin can adapt to short-term changes in diet before weight gain and may facilitate the development of obesity and associated diseases.

Fragestellung: Eine beeinträchtigte Insulinwirkung im Gehirn spielt eine zentrale Rolle in der Pathophysiologie von T2D [1]. Noch unklar ist, ob die Insulinresistenz im Gehirn Ursache oder Folge eines gestörten Glukosestoffwechsels darstellt. Adipositas und Überernährung begünstigen eine Gehirninsulinresistenz [2], wobei hedonischer Appetit mit einem höheren BMI korreliert [3]. Forschungen ergaben, dass eine transkranielle Gleichstromstimulation (engl.: tDCS) die kortikale Gehirnaktivität modulieren kann [4]. Auf Verhaltensebene zeigte sich, dass eine anregende tDCS die Selbstkontrolle erhöhen und den hedonischen Appetit, insbesondere das Verlangen nach Süßspeisen, mindert [5]. Bislang ist jedoch noch unerforscht, inwiefern eine Stimulation von insulinsensitiven Gehirnarealen die tatsächlich aufgenommene Nahrungsmenge beeinflussen kann.

CONTEXT:Central insulin has been shown to regulate eating behavior and cognitive processes in a sex-specific manner. Besides memory, the hippocampus is pivotal in the control of appetite. OBJECTIVE:This work aimed to investigate how insulin interacts with the hippocampal food-cue response and evaluate the potential role of sex hormones. METHODS:Using functional magnetic resonance imaging, we evaluated task-based functional connectivity (FC) of the hippocampus during food-cue presentation in 60 participants (age: 21-69 years; 30 women) after intranasal insulin or placebo administration, in a randomized within-subject design. In an exploratory analysis, we investigated whether hippocampal FC after intranasal insulin administration is related to estradiol and progesterone levels during the follicular and luteal phase of the menstrual cycle in 13 premenopausal women (age: 20-28 years). RESULTS:Intranasal insulin increased hippocampal FC with the prefrontal cortex compared to placebo, regardless of sex. This correlated with stronger reduction in subjective feeling of hunger and food craving. Moreover, we observed an interaction between sex and nasal spray condition with higher hippocampal FC to the calcarine gyrus after insulin compared to placebo in men, while women showed a lower response. In premenopausal women, the centrally mediated effect of insulin on hippocampus to calcarine gyrus FC negatively correlated with the estradiol/progesterone ratio in the luteal phase. CONCLUSION:Central insulin influences hippocampal FC to regions vital for inhibitory control during high-caloric food-cue presentation, implying a potential role of the hippocampal network in modulating insulin's anorexic effects. The observed sex differences between the hippocampus and visual cortex might be influenced by sex hormone action.

ObjectivesIntrauterine exposure to gestational diabetes mellitus (GDM) increases the risk of obesity in the offspring, but little is known about the underlying neural mechanisms. The hippocampus is crucial for food intake regulation and is vulnerable to the effects of obesity. The purpose of the study was to investigate whether GDM exposure affects hippocampal functional connectivity during exposure to food cues using functional magnetic resonance imaging (fMRI).MethodsParticipants were 90 children age 7-11 years (53 females) who underwent an fMRI-based visual food cue task in the fasted state. Hippocampal functional connectivity (FC) was examined using generalized psychophysiological interaction in response to food versus non-food cues. Hippocampal FC was compared between children with and without GDM exposure, while controlling for possible confounding effects of age, sex and waist-to-hip ratio. In addition, the influence of childhood and maternal obesity were investigated using multiple regression models.ResultsWhile viewing high caloric food cues compared to non-food cure, children with GDM exposure exhibited higher hippocampal FC to the insula and striatum (i.e., putamen, pallidum and nucleus accumbens) compared to unexposed children. With increasing BMI, children with GDM exposure had lower hippocampal FC to the somatosensory cortex (i.e., postcentral gyrus).ConclusionsIntrauterine exposure to GDM was associated with higher food-cue induced hippocampal FC especially to reward processing regions. Future studies with longitudinal measurements are needed to clarify whether altered hippocampal FC may raise the risk of the development of metabolic diseases later in life.

The hypothalamus is the key regulator for energy homeostasis and is functionally connected to striatal and cortical regions vital for the inhibitory control of appetite. Hence, the ability to non-invasively modulate the hypothalamus network could open new ways for the treatment of metabolic diseases. Here, we tested a novel method for network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in the control of appetite. Based on the resting-state functional connectivity map of the hypothalamus, a 12-channel net-tDCS protocol was generated (Neuroelectrics Starstim system), which included anodal, cathodal and sham stimulation. Ten participants with overweight or obesity were enrolled in a sham-controlled, crossover study. During stimulation or sham control, participants completed a stop-signal task to measure inhibitory control. Overall, stimulation was well tolerated. Anodal net-tDCS resulted in faster stop signal reaction time (SSRT) compared to sham (p = 0.039) and cathodal net-tDCS (p = 0.042). Baseline functional connectivity of the target network correlated with SSRT after anodal compared to sham stimulation (p = 0.016). These preliminary data indicate that modulating hypothalamus functional network connectivity via net-tDCS may result in improved inhibitory control. Further studies need to evaluate the effects on eating behavior and metabolism.

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking "sweets" can be associated with weight gain, but the relationship between sweet taste preference and hypothalamic regulation of appetite is unknown. This study tested the hypothesis that sweet taste preference is associated with increased hypothalamic activation in response to glucose (a purported neural marker for weight gain risk) and greater longitudinal increases in body mass index (BMI). Fifty-four adults aged 18-35 years with a mean (& PLUSMN; SD) BMI of 27.99 & PLUSMN; 5.32 kg/m2 completed the study. Height and weight were measured at baseline and 6-12 months later in a subset of 36 participants. Sweet taste preference was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and after oral glucose ingestion to determine hypothalamic blood flow response to glucose. Linear models were used to examine relationships between sweet taste preference and the hypothalamic response to glucose and longitudinal changes in BMI, adjusting for age, sex, and baseline BMI. Sweet taste preference was positively associated with glucose-linked hypothalamic blood flow (beta = 0.017, p = 0.043), adjusted for age, sex and BMI. We also observed a positive association between sweet taste preference and longitudinal change in BMI (beta = 0.088, p = 0.015), adjusted for age, sex and baseline BMI. These findings suggest that heightened sweet taste preference is associated with glucose-linked hypothalamic activation and may be linked to increased susceptibility for weight gain.

Aims: Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. Materials and Methods: We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m(2), age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions). Results: We found significant negative associations between age and insulin action in the hippocampus (beta = -0.215; p = .017) and caudate nucleus (beta = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (beta = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (beta = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions. Conclusion: We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.