In healthy young lean, but also in overweight and obese participants, intranasal insulin acutely enhanced functional connectivity between the prefrontal regions of the DMN and the hippocampus. These regions are known to be crucial for higher cognitive processes. Interestingly, we found increased dorsal medial PFC-hippocampal functional connectivity to significantly modulate hunger. This insulin-induced increase acted as a mediator between individual’s visceral adipose tissue, a metabolic unfavorable abdominal fat depot, and subjective feeling of hunger. Participants with a stronger increase in functional connectivity felt less hungry 120 minutes after insulin administration. Furthermore, individuals with more visceral adipose tissue were hungrier. This relationship was suppressed by the increase in functional connectivity between the dorsal medial PFC and hippocampus. Moreover, the connection between metabolic and cognitive centers of the brain could be boosted by intranasal insulin, however only in participants with high peripheral insulin sensitivity. The higher the peripheral insulin sensitivity index, the stronger the increase in functional connectivity between the anterior medial prefrontal cortex of the DMN and the hypothalamus after insulin administration.

Neuroimaging studies investigating target brain regions of insulin action, using endogenous and exogenous stimulation of insulin, have identified the hypothalamus, striatal and frontal regions to be particularly insulin sensitive4, 7. Specifically, in response to glucose ingestion, individuals with a higher increase in endogenous insulin showed a more pronounced prefrontal cortex activity decrease to food cues37, 42, 43. Similarly, the PFC and hypothalamus neural activity attenuated in response to intranasal insulin11, 15, 39. Moreover, not just localized neural activation but also functional connectivity of the hypothalamus and PFC can be modulated by glucose43, 44 or by meal ingestion45,46,47. In the fasting compared to the fed state46 hypothalamic-PFC functional connectivity was enhanced, while the ingestion of a meal reduced functional connectivity to the medial and lateral PFC45, 47. Interestingly, other hormonal interventions with leptin48, 49 or intranasal oxytocin50,51,52 have likewise shown to alter PFC functional connectivity. Leptin replacement therapy in patients with lipodystrophy, for example, significantly increased hypothalamic-PFC functional connectivity accompanied by normalization of eating behavior49. Accordingly, in the current study we found the functional connection between the anterior medial PFC and the hypothalamus to increase in participants with favorable peripheral insulin sensitivity. Hence, evidence accumulates that brain-periphery interactions play an important role in the regulation of eating behavior and metabolism. With respect to insulin action, recent studies have shown that the prefrontal and hypothalamic response to insulin stimulation are significantly correlated with peripheral insulin sensitivity11, 15, 37, 39, 42. Moreover, intranasal insulin delivery to the brain improved peripheral insulin sensitivity in placebo-controlled hyperinsulinemic-euglycemic glucose clamps15, 53. This coincides with the current finding that central insulin administration can enhance the functional connectivity between cognitive and homeostatic brain centers in peripherally insulin sensitive individuals.

The insulin-induced heightened functional connectivity between the prefrontal regions of the DMN and the hippocampus was independent of peripheral IR. Lean, overweight and obese participants with poor and high peripheral insulin sensitivity showed an increase in functional connectivity after intranasal insulin administration. Consistent with this notion, Fadel and Reagan25 proposed that hippocampal IR may occur independent of peripheral IR. Rats with hippocampal-specific IR showed no changes in body weight and peripheral insulin sensitivity, however changes in neural plasticity and impaired spatial learning54. Interestingly, in the current study, we observed a link between central insulin action in the hippocampus and metabolism and hunger. The increased hippocampal functional connectivity acted as a mediator between perceived hunger and visceral adipose tissue. This is in line with animal and humans studies showing that the hippocampus processes visceral energy-status relevant information detecting interoceptive signals of hunger and satiety55, 56. Hippocampal neurons form memory of a meal and are involved in inhibitory effects of recent eating on subsequent food consumption56, 57. Concomitantly, patients with hippocampal lesions will rate their subjective state of hunger in the middle of the magnitude scale independent of when the last meal was consumed55, 58. Moreover, reduced sensitivity to internal signals is found in obesity59 and in individuals with high western diet consumption60. Specifically participants with self-reported high fat and high refined-sugar diet performed poorer on hippocampal sensitive memory tasks and were less accurate in recalling what they had previously eaten60. Free-fatty acids (FFAs), which can be mildly suppressed by intranasal insulin61, may mediate the relationship between visceral adipose tissue and brain insulin responsiveness. Specifically, elevated levels of saturated nonesterified fatty acids led to a diminished insulin reactivity in theta frequency activity generated in the hippocampus62. Hence, it is possible that circulating FFAs in individuals with high visceral adipose tissue interferes with the subjective feeling of hunger. Enhancing hippocampal functional connectivity by means of centrally acting insulin could potentially breach this viscous cycle improving internal awareness for hunger. Hence, we propose that the beneficial effects of boosting hippocampal functional connectivity with intranasal insulin go beyond improving cognition, as recently reported31. It can potentially improve metabolism by enhancing the sensitivity to internal signals, thereby reducing perceived hunger. Hence, intranasal insulin could be a potential therapeutic tool to improve memory formation for food and raise internal awareness for satiety and hunger signals.

While solid evidence exists that obesity-associated IR affects at least parts of the DMN4, the current study showed for the first time that DMN functional connectivity plays a pivotal role in central insulin action in cognitively healthy young adults. The prefrontal part of the DMN, in particular, may constitute a link between networks controlling insulin-mediated effects on metabolism and cognition. However, besides brain IR, peripheral IR seems to play an important role in DMN function. Even in cognitively intact prediabetes and T2D patients, the severity of peripheral IR is related to altered brain function in regions of the DMN showing reduced cerebral blood flow and disrupted functional connectivity63. Interestingly, treated T2D patients do not show reduced cerebral blood flow in the DMN compared to the insulin resistant controls64. Hence, it could be that altered brain functions in regions of the DMN is a consequence of peripheral IR rather than a cause of brain IR. Concurrently, we identified obesity-associated changes in functional connectivity in the posterior part of the DMN, which was not influenced by intranasal insulin. Hence, we propose the anterior part of the DMN to constitute an overlap between peripheral and central IR. However, further studies are necessary to investigate cause and consequences of central and peripheral IR.

A limitation of the study is the missing examinations on cognitive functions. All of our participants were students at the university and displayed no psychiatric or neurological illness. Furthermore, we used a thorough metabolic screening to exclude type 2 diabetes and other alterations associated with the metabolic syndrome. Nonetheless, to further link metabolic and cognitive endpoints of brain insulin action, further studies are necessary evaluating metabolism as well as cognition. Moreover, we cannot rule out a possible spillover of intranasal insulin into the peripheral blood15, 53, 65. More frequent blood sampling is needed to detect this phenomenon. We recently characterized this spillover at systemic elevated insulin levels. Even after mimicking the spillover effect during the placebo condition, intranasal insulin still significantly mediated whole-body metabolism53. However, no detailed kinetics have yet been reported at fasting insulin levels.

Taken together, we were able to show that acute administration of intranasal insulin administration can enhance DMN functional connectivity in healthy lean, overweight and obese adults. The insulin induced increase in dorsal medial PFC-hippocampal functional connectivity served as a mediator, suppressing the relationship between visceral adipose tissue and hunger. Furthermore, we observed a significant brain-periphery interaction of insulin action. Only individuals with an insulin-induced DMN-hypothalamic functional connectivity change revealed favorable peripheral insulin sensitivity. Therefore, enhancing brain functional connectivity using intranasal insulin has potential to boost cognition and metabolism. The relevance of our findings for the treatment of obesity and metabolic disease is currently however still speculative. Our results point to a novel mechanism of how brain insulin action facilitates weight loss by enhancing brain functional connectivity and reducing perceived hunger. Hence, intranasal insulin could be a potential therapeutic tool to improve internal awareness for satiety and hunger signals. Further intervention studies have to be conducted to demonstrate who will benefit from enhancing brain insulin action.