Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse

Abstract

Non-technical summary Obesity is known to result from energy intake in excess of expenditure. What is not known is how individuals are able to eat in excess of their energy needs. We show that after chronic consumption of a high fat diet (which causes obesity), intestinal sensory nerves are less responsive to chemicals released from the gut during a meal (cholecystokinin and 5-hydroxytryptamine) as well as to distension of the gut as might occur during a meal. This appears to be due to the fact that the ability of the nerve cells to be excited is impaired. This suggests that consumption of an unhealthy diet that leads to obesity causes decreased signalling from the intestine, which may lead to increased food intake and contribute to further weight gain, or allow the maintenance of excess weight and obesity.Abstract Gastrointestinal vagal afferents transmit satiety signals to the brain via both chemical and mechanical mechanisms. There is indirect evidence that these signals may be attenuated in obesity. We hypothesized that responses to satiety mediators and distension of the gut would be attenuated after induction of diet induced obesity. Obesity was induced by feeding a high fat diet (60% kcal from fat). Low fat fed mice (10% kcal from fat) served as a control. High fat fed mice were obese, with increased visceral fat, but were not hyperglycaemic. Recordings from jejunal afferents demonstrated attenuated responses to the satiety mediators cholecystokinin (CCK, 100 nM) and 5-hydroxytryptamine (5-HT, 10 μM), as was the response to low intensity jejunal distension, while responses to higher distension pressures were preserved. We performed whole cell patch clamp recordings on nodose ganglion neurons, both unlabelled, and those labelled by fast blue injection into the wall of the jejunum. The cell membrane of both labelled and unlabelled nodose ganglion neurons was less excitable in HFF mice, with an elevated rheobase and decreased number of action potentials at twice rheobase. Input resistance of HFF neurons was also significantly decreased. Calcium imaging experiments revealed reduced proportion of nodose ganglion neurons responding to CCK and 5-HT in obese mice. These results demonstrate a marked reduction in afferent sensitivity to satiety related stimuli after a chronic high fat diet. A major mechanism underlying this change is reduced excitability of the neuronal cell membrane. This may explain the development of hyperphagia when a high fat diet is consumed. Improving sensitivity of gastrointestinal afferent nerves may prove useful to limit food intake in obesity.

The modulatory role of high fat feeding on gastrointestinal signals in obesity

“…HF maintained rats display decreased hindbrain and enteric neuronal Fos-Li after exogenous CCK-8 administration, indicating a decrease in neuronal activation [77]; although the exact site where these alterations occur is still under investigation. Extracellular recordings from jejunal vagal afferents of HF fed mice showed decreased responses to CCK-8, in addition to an overall decrease in the cell membrane excitability in intestine-projecting nodose neurons [120]. Furthermore, there was a 65% decrease in the number of nodose neurons responsive to CCK [120].…”

“…Extracellular recordings from jejunal vagal afferents of HF fed mice showed decreased responses to CCK-8, in addition to an overall decrease in the cell membrane excitability in intestine-projecting nodose neurons [120]. Furthermore, there was a 65% decrease in the number of nodose neurons responsive to CCK [120]. This decrease in responsiveness to CCK is mediated by CCK-1 receptor (CCK-1R) located on vagal afferents.…”

The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH

“…It is generally recognized that activation of vagal sensory afferents of nodose neurons that innervate most visceral organs either mechanically or chemically evokes sympatho-inhibitory and parasympathetic reflexes (1)(2)(3)(4)(5)(6)(7). Conversely, excitation of the DRG spinal afferents induces excitatory sympathetic reflexes (8).…”

Ongoing ingestive behavior is rapidly suppressed by a preabsorptive, intestinal “bitter taste” cue

“…Such interest has only been reinforced by the mounting evidence that post-oral satiety signals are disrupted in obesity (e.g., 9,10,12,13). While the anatomical and molecular correspondences have accordingly inspired a rethinking of how chemicals are detected and encoded by post-oral chemoreceptors to affect physiological, and possibly behavioral, controls of intake, these speculations have outpaced experimental analysis.…”