like peptide (GLP)-1 is secreted rapidly from the intestine postprandially. We therefore investigated its possible neural regulation. With the use of isolated perfused porcine ileum, GLP-1 secretion was measured in response to electrical stimulation of the mixed, perivascular nerve supply and infusions of neuroactive agents alone and in combination with different blocking agents. Electrical nerve stimulation inhibited GLP-1 secretion, an effect abolished by phentolamine. Norepinephrine inhibited secretion, and phentolamine abolished this effect. GLP-1 secretion was stimulated by isoproterenol (abolished by propranolol). Acetylcholine stimulated GLP-1 secretion, and atropine blocked this effect. Dimethylphenylpiperazine stimulated GLP-1 secretion. In chloralose-anesthetized pigs, however, electrical stimulation of the vagal trunks at the level of the diaphragm had no effect on GLP-1 or GLP-2 and weak effects on glucose-dependent insulinotropic peptide and somatostatin secretion, although this elicited a marked atropine-resistant release of the neuropeptide vasoactive intestinal polypeptide to the portal circulation. Thus GLP-1 secretion is inhibited by the sympathetic nerves to the gut and may be stimulated by intrinsic cholinergic nerves, whereas the extrinsic vagal supply has no effect. somatostatin; nerve stimulation; enteric nervous system; vasoactive intestinal polypeptide; incretin hormones GLUCAGON-LIKE PEPTIDE (GLP)-1 is a peptide primarily produced in the lower part of the gut (reviewed in Ref. 22). It is known as an incretin hormone (stimulating insulin secretion) (27) and thought to be part of the "ileal brake" mechanism (inhibition of upper gut motility and secretion elicited by the presences of unabsorbed nutrients in the ileum) (28,32,44). Thus infusions of GLP-1 have been shown to reduce appetite and energy intake in humans (14). Relatively little is known about the mechanisms that regulate GLP-1 secretion in pigs and humans.The presence of unabsorbed nutrients in the lumen seems to be an important stimulus for GLP-1 secretion in rats (38), pigs (23), and humans (28). However, the response to a meal is usually rapid, with increases in the plasma concentration occurring within a few minutes after the start of meal ingestion (6,10,24,34,38), before the bulk of the meal is thought to have reached the lower gut. This suggests that a neural and/or an endocrine pathway from the upper part of the gastrointestinal tract to the lower gut may exist.In rats, glucose-dependent insulinotropic peptide (GIP) has been shown to stimulate GLP-1 secretion (9,20,35,38), although recent studies have indicated that a neural pathway involving the vagus nerve (2, 39) might predominate compared with a direct endocrine pathway. Infusions of muscarinic cholinergic agonists into isolated perfused rat ileum and colon resulted in stimulation of GLP-1 secretion (9,19,35), and studies in anesthetized rats and in fetal rat intestinal cells suggested that both M1 and M2 muscarinic receptors could be involved in control of GLP-1 rel...

No abstract

Abundant long‐lived liver‐resident macrophages, termed Kupffer cells, are activated during chronic liver injury. They secrete both pro‐inflammatory and pro‐fibrotic cytokines, which act on hepatic stellate cells causing their transdifferentiation into myofibroblasts that deposit collagen. In other tissues, wound‐associated macrophages go further, and transdifferentiate into fibrocytes, secreting collagen themselves. We tested Kupffer cells for this property in two experimental models: mixed non‐parenchymal cell culture, and precision‐cut liver slice culture. Using the Emr1‐Cre transgene as a driver and the RiboTag transgene as a reporter, we found that Kupffer cells undergo transdifferentiation under these circumstances. Over time, they lose the expression of both Kupffer cell‐specific and macrophage‐specific genes and the transcription factors that control their expression, and they begin to express multiple genes and proteins characteristic of either myofibroblasts or tissue fibroblasts. These effects were strongly conserved between non‐parenchymal cell culture and liver tissue slice culture, arguing that such transdifferentiation is a conserved function of Kupffer cells. We conclude that in addition to supporting fibrosis through an action on stellate cells, Kupffer cells also participate in liver fibrosis through transdifferentiation into fibrocytes.

In mice, a subset of cardiac macrophages and Kupffer cells derive from fetal precursors, seed the developing tissues, self-renew locally, and persist into adulthood. In this study we investigated how these cells survive acute systemic inflammation. In both tissues, early-derived subsets rapidly responded to acute systemic inflammation by assuming a temporary nonclassical activation state featuring upregulation of both proinflammatory (Il1b, Tnf, Nfkb1), and anti-inflammatory (Il10, Il4ra, Nfkbiz) genes. During this process, transcription factor genes associated with myeloid identity (Spi1, Zeb2) were upregulated, whereas those associated with tissue specificity (Nr1h3 for Kupffer cells and Nfatc2 and Irf4 for cardiac macrophages) were downregulated, suggesting that the cells reasserted their myeloid identity but renounced their tissue identity. Most of these changes in gene expression reverted to steady-state levels postresolution. We conclude that these early-derived macrophage subsets are resilient in the face of acute stress by temporary loss of adaptation to local tissue-specific niches while reasserting their generic myeloid identity.