Intranasal Insulin Modulates Intrinsic Reward and Prefrontal Circuitry of the Human Brain in Lean Women

Kullmann, Stephanie; Frank, Stefanie; Heni, Martin; Ketterer, Caroline; Veit, Ralf; Häring, Hans‐Ulrich; Fritsche, Andreas; Preißl, Hubert

doi:10.1159/000341406

Cited by 91 publications

(99 citation statements)

References 52 publications

(66 reference statements)

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“…Furthermore, individuals' endogenous serum insulin levels determined the reactivity of limbic regions and the prefrontal cortex to food cues after glucose ingestion (31,32). Exogenous intranasal insulin had comparable effects and reduced resting state prefrontal cortex activity in lean women (8). Concurrently, we found intranasal insulin to induce a differential pattern, reducing prefrontal cortex CBF in lean participants and increasing it in obese participants.…”

Section: Discussionmentioning

confidence: 58%

Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

et al. 2015

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OBJECTIVEImpaired 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 METHODSIn 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. RESULTSIn 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. CONCLUSIONSBrain 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.

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Section: Discussionmentioning

confidence: 58%

Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

et al. 2015

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“…1D], and had increased entries to the food zone [t (14) = 2.16, P = 0.04; Fig. 1 E and F], but only when food was present [F (1,28) = 8.86, P = 0.0060; Fig. 1F and Movies S1 and S2].…”

Section: Resultsmentioning

confidence: 99%

“…S1), suggesting that 24-h SHF does not influence anxiety or locomotor activity. Finally, mice with prior access to 24-h SHF consumed more food after the test [F (1,28) = 6.40, P = 0.017; Fig. 1G].…”

Section: Resultsmentioning

confidence: 99%

Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA

Liu

Globa

Mills

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In an environment with easy access to highly palatable and energydense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.palatable food | synaptic density | VTA | dopamine | excitatory synaptic transmission P riming effects of food-related advertising (1) and consumption of palatable food (2, 3) can drive sated consumption of food. Overconsumption of food relative to need is an important factor in the development of obesity (4). The priming effects of palatable food on food intake are likely a considerable factor in the obesity epidemic. However, the mechanism by which food-priming effects occur is unknown. The ventral tegmental area (VTA) and its mesolimbic projections are critical for learning about environmental cues used to predict motivationally relevant outcomes (5). Indeed, food-related cues activate the dopaminergic circuit to reinforce food intake (6, 7). VTA dopamine neurons can increase or decrease their synaptic efficacy to modulate their consequent dopaminergic output (8, 9). The strength of excitatory synaptic input onto VTA dopamine neurons plays a central role in rewardrelated behavior with potentiation of synapses formed onto VTA neurons, facilitating the transformation of neutral environmental stimuli into salient reward predictive cues (8). Conversely, depression of excitatory synaptic transmission would likely reduce the intrinsic firing rate and excitability of dopamine neurons, as has been demonstrated for other neurons (10), and would likely reduces the salience of reward predicting cues.The motivation to eat is regulated by a variety of intrinsic and extrinsic factors. Metabolic signals, including neuronal or circulating peptides released in response to internal states such as hunger ...

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“…Previously, we demonstrated that intranasal insulin regulates hypothalamic activity in lean women (16). In animals, specific hypothalamic neurons are crucial for the control of peripheral metabolism by insulin (1,4,5,7).…”

Section: Discussionmentioning

confidence: 96%

“…One technique to selectively introduce brain insulin effects is to apply insulin as a nasal spray to bypass the blood-brain barrier and cause significant and sustained elevations of insulin concentrations in the cerebrospinal fluid without major effects on peripheral insulin levels (15). It significantly influences activity in specific brain areas (13,16), including the hypothalamus, the central regulator of metabolism (16). Of note, people do not uniformly react to central insulin application.…”

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confidence: 99%

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

et al. 2014

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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 wholebody 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.

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Intranasal Insulin Modulates Intrinsic Reward and Prefrontal Circuitry of the Human Brain in Lean Women

Cited by 91 publications

References 52 publications

Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

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