Sweet taste preference is associated with greater hypothalamic response to glucose and longitudinal weight gain.

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 (± SD) BMI of 27.99 ± 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.

The effect of hunger state on hypothalamic functional connectivity in response to food cues.

The neural underpinnings of the integration of internal and external cues that reflect nutritional status are poorly understood in humans. The hypothalamus is a key integrative area involved in short- and long-term energy intake regulation. Hence, we examined the effect of hunger state on the hypothalamus network using functional magnetic resonance imaging. In a multicenter study, participants performed a food cue viewing task either fasted or sated on two separate days. We evaluated hypothalamic functional connectivity (FC) using psychophysiological interactions during high versus low caloric food cue viewing in 107 adults (divided into four groups based on age and body mass index [BMI]; age range 24-76 years; BMI range 19.5-41.5 kg/m2 ). In the sated compared to the fasted condition, the hypothalamus showed significantly higher FC with the bilateral caudate, the left insula and parts of the left inferior frontal cortex. Interestingly, we observed a significant interaction between hunger state and BMI group in the dorsolateral prefrontal cortex (DLPFC). Participants with normal weight compared to overweight and obesity showed higher FC between the hypothalamus and DLPFC in the fasted condition. The current study showed that task-based FC of the hypothalamus can be modulated by internal (hunger state) and external cues (i.e., food cues with varying caloric content) with a general enhanced communication in the sated state and obesity-associated differences in hypothalamus to DLPFC communication. This could potentially promote overeating in persons with obesity.

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial.

OBJECTIVE: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS: Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.

Resting-state functional connectivity of the human hypothalamus.

Communication pathways of the hypothalamus with other brain regions and the periphery are critical to successfully control key physiological and psychological processes. With advanced functional magnetic resonance imaging (fMRI) techniques, it is possible to target hypothalamic function and infer discrete hypothalamus networks. Resting-state functional connectivity (RSFC) is a promising tool to study the functional organization of the brain and may act as a marker of individual differences and dysfunctions. Based on recent fMRI findings, the hypothalamus is mostly connected to parts of the striatum, midbrain, thalamus, insula, frontal, cingulate, and temporal cortices and the cerebellum. There is a strong interplay of the hypothalamus with these regions in response to different metabolic, hormonal, and nutritional states. In a state of hunger, hypothalamus RSFC increases with a strong shift to reward-related brain regions, especially in person with excessive weight. Nutrient signals and hormones, as insulin, act on these same connections conveying reward and internal signals to regulate homeostatic control. Moreover, dysfunctional hypothalamus communication has been documented in persons with neurological and psychiatric diseases. The results implicate that patients with depression, epilepsy, and neurodegenerative diseases show mostly a reduction in hypothalamus RSFC, whereas patients with migraine and headache display predominantly increased hypothalamus RSFC. The extent of these changes and regions affected depend on the disorder and symptom severity. Whether hypothalamus RSFC can serve as a marker for disease states or is a prodromal neurobiological feature still needs to be investigated.

No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men.

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.

Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans.

BACKGROUND: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. METHODS: Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. RESULTS: Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, ß = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, ß = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. CONCLUSIONS: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.

Leptin Replacement Reestablishes Brain Insulin Action in the Hypothalamus in Congenital Leptin Deficiency.

OBJECTIVE: Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism. RESEARCH DESIGN AND METHODS: In a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution. RESULTS: After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group. In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity. CONCLUSIONS: Leptin replacement and weight loss improved homeostatic insulin action in the patient in question.

Hypothalamic insulin responsiveness is associated with pancreatic insulin secretion in humans.

CONTEXT: Activity of the hypothalamus - the major brain area controlling peripheral metabolism - is specifically modulated by insulin. Research in animals suggests that brain insulin action influences pancreatic insulin secretion. OBJECTIVE: We investigated the association between hypothalamic insulin sensitivity and pancreatic insulin secretion in humans. DESIGN AND SETTING: This was a clinical-experimental trial in an university hospital setting. PARTICIPANTS: 48 healthy volunteers (21 women and 27 men) were included. MAIN OUTCOME MEASURES: Insulin sensitivity of the hypothalamus was quantified by cerebral blood flow (CBF) using MRI in combination with intranasal insulin administration. On a different day, a 75g oral glucose tolerance test with glucose, insulin, and C-peptide levels measured at five time points was performed. Three established insulin secretion indices (insulinogenic index [IGI], corrected insulin response [CIR], and AUCC-peptide0-30/AUCglucose0-30) were then analyzed for correlations with hypothalamic insulin sensitivity independent of whole-body insulin sensitivity. RESULTS: Hypothalamic insulin sensitivity showed a significant association with all three investigated insulin secretion indices (IGI p=0.0043; CIR p=0.06; AUCCpep0-30/AUCgluc0-30 p=0.0179). Participants with a strong hypothalamic insulin effect (i.e. decreased CBF after intranasal insulin administration) had lower insulin secretion during the OGTT, whereas participants with hypothalamic insulin resistance had substantially higher insulin secretion. No correlations with the occipital cortex, a control region, were detected. CONCLUSIONS: Our data suggest that hypothalamic insulin resistance might contribute to pancreatic insulin hypersecretion. Alternatively, common pathogenetic mechanisms could introduce both brain insulin resistance and beta cell hypersecretion.

Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men.

Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis.

Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults.

OBJECTIVE: Impaired brain insulin action has been linked to obesity, type 2 diabetes, and neurodegenerative diseases. To date, the central nervous effects of insulin in obese humans still remain ill defined, and no study thus far has evaluated the specific brain areas affected by insulin resistance. RESEARCH DESIGN AND METHODS: In 25 healthy lean and 23 overweight/obese participants, we performed magnetic resonance imaging to measure cerebral blood flow (CBF) before and 15 and 30 min after application of intranasal insulin or placebo. Additionally, participants explicitly rated pictures of high-caloric savory and sweet food 60 min after the spray for wanting and liking. RESULTS: In response to insulin compared with placebo, we found a significant CBF decrease in the hypothalamus in both lean and overweight/obese participants. The magnitude of this response correlated with visceral adipose tissue independent of other fat compartments. Furthermore, we observed a differential response in the lean compared with the overweight/obese group in the prefrontal cortex, resulting in an insulin-induced CBF reduction in lean participants only. This prefrontal cortex response significantly correlated with peripheral insulin sensitivity and eating behavior measures such as disinhibition and food craving. Behaviorally, we were able to observe a significant reduction for the wanting of sweet foods after insulin application in lean men only. CONCLUSIONS: Brain insulin action was selectively impaired in the prefrontal cortex in overweight and obese adults and in the hypothalamus in participants with high visceral adipose tissue, potentially promoting an altered homeostatic set point and reduced inhibitory control contributing to overeating behavior.

Resting-state functional connectivity of the human hypothalamus.

The hypothalamus is of enormous importance for multiple bodily functions such as energy homeostasis. Especially, rodent studies have greatly contributed to our understanding how specific hypothalamic subregions integrate peripheral and central signals into the brain to control food intake. In humans, however, the neural circuitry of the hypothalamus, with its different subregions, has not been delineated. Hence, the aim of this study was to map the hypothalamus network using resting-state functional connectivity (FC) analyses from the medial hypothalamus (MH) and lateral hypothalamus (LH) in healthy normal-weight adults (n = 49). Furthermore, in a separate sample, we examined differences within the LH and MH networks between healthy normal-weight (n = 25) versus overweight/obese adults (n = 23). FC patterns from the LH and MH revealed significant connections to the striatum, thalamus, brainstem, orbitofrontal cortex, middle and posterior cingulum and temporal brain regions. However, our analysis revealed subtler distinctions within hypothalamic subregions. The LH was functionally stronger connected to the dorsal striatum, anterior cingulum, and frontal operculum, while the MH showed stronger functional connections to the nucleus accumbens and medial orbitofrontal cortex. Furthermore, overweight/obese participants revealed heightened FC in the orbitofrontal cortex and nucleus accumbens within the MH network. Our results indicate that the MH and LH network are tapped into different parts of the dopaminergic circuitry of the brain, potentially modulating food reward based on the functional connections to the ventral and dorsal striatum, respectively. In obese adults, FC changes were observed in the MH network.

Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men.

Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on whole-body insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.

Olive oil aroma extract modulates cerebral blood flow in gustatory brain areas in humans.

BACKGROUND: Low- and high-fat meals affect homeostatic and gustatory brain areas differentially. In a previous study, we showed that a high-fat meal decreased cerebral blood flow (CBF) in homeostatic brain areas (hypothalamus), whereas a low-fat meal increased CBF in gustatory regions (anterior insula). OBJECTIVE: The aim of this study was to investigate the long-lasting effect of fat-free flavor-active compounds of olive oil on the brain and whether those aroma components can trigger fat-associated brain responses in homeostatic and gustatory regions. DESIGN: Eleven healthy male subjects participated in a functional magnetic resonance imaging study. On 2 measurement days, subjects consumed single-blinded a plain low-fat yogurt or low-fat yogurt mixed with a fat-free aroma extract of olive oil. Resting CBF was measured before and 30 and 120 min after yogurt intake. Hunger was rated before each measurement. Blood samples were collected at 6 time points. RESULTS: The extract-containing yogurt elicited higher CBF in the frontal operculum 30 and 120 min after a meal. Furthermore, the activity change in the anterior insula after 30 min correlated positively with the glucose change in the extract condition only. No effects were observed in the hypothalamus. CONCLUSIONS: The anterior insula and the frontal operculum are regarded as the primary taste cortex. Modulation of the frontal operculum by the yogurt containing the olive oil extract suggests that it might be possible to simulate fat-triggered sensations in the brain on the gustatory level, possibly by ingredients the body implicitly associates with fat. This trial was registered at clinicaltrials.gov as NCT01716286.

Fat intake modulates cerebral blood flow in homeostatic and gustatory brain areas in humans.

BACKGROUND: The hypothalamus is the central homeostatic control region of the brain and, therefore, highly influenced by nutrients such as glucose and fat. Immediate and prolonged homeostatic effects of glucose ingestion have been well characterized. However, studies that used stimulation with fat have mainly investigated immediate perceptional processes. Besides homeostatic processes, the gustatory cortex, including parts of the insular cortex, is crucial for the processing of food items. OBJECTIVE: The aim of this study was to investigate the effect of high- compared with low-fat meals on the hypothalamus and the insular cortex. DESIGN: Eleven healthy men participated in a single-blinded, functional MRI study of high- and low-fat meals on 2 measurement days. Cerebral blood flow (CBF) was measured before and 30 and 120 min after intake of high- and low-fat yogurts. Hunger was rated and blood samples were taken before each CBF measurement. RESULTS: High-fat yogurt induced a pronounced decrease in CBF in the hypothalamus, and the corresponding CBF change correlated positively with the insulin change. Furthermore, insular activity increased after 120 min in the low-fat condition only. The CBF change in both regions correlated positively in the high-fat condition. CONCLUSIONS: The decrease in hypothalamic activity and the interaction with the insular cortex elicited by fat may contribute to an efficient energy homeostasis. Therefore, fat might be a modulator of homeostatic and gustatory brain regions and their interaction. This trial was registered at clinicaltrials.gov as NCT01516021.

Monounsaturated fatty acids prevent the aversive effects of obesity on locomotion, brain activity, and sleep behavior.

Fat and physical inactivity are the most evident factors in the pathogenesis of obesity, and fat quality seems to play a crucial role for measures of glucose homeostasis. However, the impact of dietary fat quality on brain function, behavior, and sleep is basically unknown. In this study, mice were fed a diet supplemented with either monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs) and their impact on glucose homeostasis, locomotion, brain activity, and sleep behavior was evaluated. MUFAs and SFAs led to a significant increase in fat mass but only feeding of SFAs was accompanied by glucose intolerance in mice. Radiotelemetry revealed a significant decrease in cortical activity in SFA-mice whereas MUFAs even improved activity. SFAs decreased wakefulness and increased non-rapid eye movement sleep. An intracerebroventricular application of insulin promoted locomotor activity in MUFA-fed mice, whereas SFA-mice were resistant. In humans, SFA-enriched diet led to a decrease in hippocampal and cortical activity determined by functional magnetic resonance imaging techniques. Together, dietary intake of MUFAs promoted insulin action in the brain with its beneficial effects for cortical activity, locomotion, and sleep, whereas a comparable intake of SFAs acted as a negative modulator of brain activity in mice and humans.