Signalling from the periphery to the brain that regulates energy homeostasis

Abstract

The CNS regulates body weight; however, we still lack a clear understanding of what drives decisions about when, how much and what to eat. A vast array of peripheral signals provides information to the CNS regarding fluctuations in energy status. The CNS then integrates this information to influence acute feeding behaviour and long-term energy homeostasis. Previous paradigms have delegated the control of long-term energy homeostasis to the hypothalamus and short-term changes in feeding behaviour to the hindbrain. However, recent studies have identified target hindbrain neurocircuitry that integrates the orchestration of individual bouts of ingestion with the long-term regulation of energy balance.

Figure 1 |. Peripheral-to-CNS signals of energy status.

Gut-secreted peptides, such as glucagon-like peptide 1 (GLP1), cholecystokinin (CCK) and peptide YY (PYY), are secreted from the gastrointestinal tract in response to nutrient ingestion. Conversely, ghrelin levels are highest during fasting and are suppressed during a meal. Leptin and insulin, secreted from adipose and pancreatic cells, respectively, circulate in proportion to adiposity and therefore represent signals of long-term energy storage. The ‘hypothalamic-centric’ view has held that long-term energy homeostasis is regulated by the hypothalamic melanocortin system (agouti-related protein (AGRP)/neuropeptide Y (NPY) neurons and pro-opiomelanocortin (POMC) neurons). Indeed, leptin and insulin regulate the activity of these neuronal populations, and at least some gut peptides may also regulate the hypothalamic melanocortin system. However, there is an increasingly appreciated role of the ascending circuits from the hindbrain to the hypothalamus that are critical in regulating both short-term and long-term energy homeostasis. ?, unidentified peptides or circuits that regulate energy homeostasis; α-MSH, α-melanocyte-stimulating hormone; AP, area postrema; ARC, arcuate nucleus; MC4-R, melanocortin receptor 4; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus.

Figure 2 |. Endocrine and neuronal pathways to the CNS.

The nodose ganglion (cell bodies of the vagus nerve) connects peripheral innervation of the stomach, intestine and portal vein to the hindbrain. These afferent nerve endings have receptors that can bind to many hormones and nutrients. Furthermore, blood flow from the intestine dumps first into the portal vein and then into the general circulation. Thus, hormones and nutrients that are increased postprandially can have endocrine or direct neural pathways to signal the CNS about the changes in nutrient status. AP, area postrema; NTS, nucleus of the solitary tract.

Figure 3 |. Roux-en Y gastric bypass and vertical sleeve gastrectomy.

In Roux-en Y gastric bypass (RYGB), there is surgical reduction of the stomach to form a small gastric pouch. The remaining 95% of the stomach remains in the peritoneal cavity. The intestinal tract is rearranged such that the mid-jejunum is anastomosed to the gastric pouch, bypassing 95% of the stomach and the whole upper gastrointestinal tract. The distal end of the duodenum is then anastomosed to the jejunum to provide biliopancreatic digestive enzymes to ingested nutrients. By contrast, vertical sleeve gastrectomy (VSG) surgically removes about 80% of the stomach along the greater curvature with no intestinal rearrangement. Adapted with permission from Kim, K. S. & Sandoval, D. A., Endocrine function after bariatric surgery, Comprehensive Physiology, John Wiley & Sons (REF. 139). Copyright © 2013 American Physiological Society.

Figure 4 |. The impact of bariatric surgery on intestinal signalling peptides.

Both Roux-en Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) increase the gastric-emptying rate (GER) and thus cause rapid nutrient access to the intestine, likely contributing to the large increase in postprandial secretions of several gut peptides, including glucagon-like peptide 1 (GLP1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP). Both surgeries also increase circulating bile acids (BAs). BAs signal via a cell-surface G-protein-coupled receptor (GPCR) called TGR5 or via a nuclear transcription factor, farnesoid X-activated receptor (FXR). Whereas TGR5 signalling is known to regulate GLP1 secretion, its role after bariatric surgery is less clear (represented by a ?). Activation of FXR leads to secretion of fibroblast growth factor 19 (FGF19; FGF15 is the mouse orthologue) from the enterocytes. After bariatric surgery, FGF15 (or FGF19) is increased, and FXR has been demonstrated to be necessary for the metabolic success of surgery in mice.