Gut fat sensing in the negative feedback control of energy balance — Recent advances
Highlights
► Small intestinal fat infusions suppress feeding via extrinsic gut sensory nerves. ► CD36, PPAR α , and oleoylethanolamide may mediate gut lipid sensing in feeding. ► Duodenal fat stimulates a gut -brain -liver circuit to affect glucose homeostasis.
Introduction
The infusion of lipid emulsions into the small intestine has been demonstrated to rapidly and potently suppress food intake in multiple mammalian species, including man [1]. A role for sensory gut innervation in this phenomenon was suggested by studies showing that local infusion of the anesthetic tetracaine blocked the ability of duodenal lipid infusions to suppress sham feeding, where ingested food drains from the stomach during a meal without impinging on the duodenum [2]. Subsequent work supported a role for luminal sensory innervation in transmitting gut lipid negative feedback signals, in that local luminal application of the neurotoxin capsaicin, which selectively affects a subpopulation of unmyelinated afferent fibers, blocked the ability of intestinal infusions the fatty acid sodium oleate to inhibit sham feeding [3]. Extrinsic afferent innervation of the gut from both vagal and non vagal sources has been implicated in the ability of duodenal lipid infusions to inhibit food intake in rodent models, as gut vagal deafferentation, as well as surgical transection of gut splanchnic nerves and removal of the celiac superior mesenteric ganglion, each blocked the ability of duodenal corn oil infusions to reduce food intake during a meal [4]. Intestinal lipid infusions at feeding inhibitory doses also stimulate c-fos expression, a marker of neuronal activation, in the caudal brainstem nucleus of the solitary tract (NTS), the central nervous system terminus of gut vagal afferents [5]. Vagal capsaicin treatment blocks the ability of gut lipids to activate brainstem NTS c-fos, further supporting a role for gut vagal afferents in determining the feeding inhibitory effects of duodenal fat infusions. Furthermore, vagal afferents supplying the jejunum have been reported to be directly activated by local infusion of lipids and fatty acids [24]. Taken together, these data suggest that the proximal gut senses lipids, and communicates information regarding gut lipid availability to the central nervous system sites important in the control of feeding behavior via extrinsic gut sensory nerves.
Recent advances in understanding the molecular and systems biology of the gut–brain axis have suggested novel candidate gut lipid sensors, and have revealed roles for lipid sensing in the control of nutrient availability by modulating hepatic glucose production. These advances are outlined below.
Section snippets
Molecular mediators of gut lipid sensing
While the precise biochemical bases for gut lipid sensing remain elusive, several studies have begun to identify locally released or expressed factors potentially important in the gut–brain feedback control of ingestion. One target is duodenal serotonin (5-HT) release acting via vagal serotonin 3 (5-HT3) ionotropic receptors. The ability of intestinal lipid infusions to inhibit food intake and activate brainstem NTS c-fos is blocked by administration of the selective 5-HT3 receptor antagonist
Gut lipid sensing in the control of glucose homeostasis
In terms of the neurobiological controls of feeding, gut lipid detection has largely been construed as a sensory capability important in generating neuroendocrine negative feedback signals that limit food intake. From physiological and behavioral perspectives, the delivery of energy dense lipid into the gastrointestinal tract functions in part to limit further nutrient availability by terminating an ongoing meal. More broadly, new studies suggest that gut lipid sensing may play a significant
Acknowledgements
This work was supported by NIH DK066618, DK020541 and the Skirball Institute for Nutrient Sensing.
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2015, Cell MetabolismCitation Excerpt :One study even suggests that fatty acids act directly on GPR40 expressed on vagal afferents to suppress food intake (Darling et al., 2014), bypassing gut peptide secretion and adding to the complexity of intestinal nutrient sensing. Nevertheless, activation of this vagal gut-brain axis is vital for nutrient-triggered negative feedback, since treating the gut with anesthetics, neurotoxins, or vagotomy abolishes the effects of intestinal nutrients on food intake and glucose regulation (Schwartz, 2011). Vagal afferent fibers terminate in the nucleus tractus solitarius (NTS) of the hindbrain, and antagonism of N-methyl-D-aspartate (NMDA) receptors in the NTS reverses the effects of intestinal nutrients or CCK to lower food intake or suppress HGP (Cheung et al., 2009; Wang et al., 2008; Wright et al., 2011).
Role of anorectic N-acylethanolamines in intestinal physiology and satiety control with respect to dietary fat
2014, Pharmacological ResearchCitation Excerpt :Dietary fat may also be sensed on the tongue [19]. Generally it is known that infusion of free fatty acids or triacylglycerol into the intestinal lumen induce a satiation effect [20–23], but on the other hand prolonged intake of dietary fat is known to promote obesity in humans and in laboratory animals [24–26]. N-Acylethanolamines (NAEs) is a group of endogenous lipid molecules that can be considered to have a second messenger-like function within the cells [27] more or less comparable to that of diacylglycerol.
How important are satiation and satiety for weight regulation?
2013, Satiation, Satiety and the Control of Food IntakeA fatty gut feeling
2013, Trends in Endocrinology and MetabolismCitation Excerpt :In rats, this satiating action is abrogated by removal of the afferent nerves that connect the gastrointestinal tract to the brain [14], and is accompanied by activation of vagal afferents in the gut [15] and neurons in the NST [16]. The local release of two well-known gut hormones, cholecystokinin and serotonin, has been implicated in these responses [17]. New evidence suggests, however, an important role for a different class of signaling molecules – the amides of fatty acids (FAs) with ethanolamine (fatty acid ethanolamides, FAEs) (Figure 1).