Glucagon‐like peptide‐2 mobilizes lipids from the intestine by a systemic nitric oxide‐independent mechanism

Xiao, Changting; Stahel, Priska; Morgantini, Cecilia; Nahmias, Avital; Dash, Satya; Lewis, Gary F.

doi:10.1111/dom.13839

Cited by 14 publications

(17 citation statements)

References 38 publications

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“…Blunting IRF5 expression results in hepatoprotection through early upregulation of anti-apoptotic and immunoregulatory signaling, increasing T Reg differentiation and IL-10 secretion upon hepatocellular stress (79). Recent research is delving into potential non-inflammatory or non-immune signaling efferent from KCs, notably effector molecules such as insulin-like growth factor-binding protein (IGFBP)-7, regulates insulin sensitivity in the context of obesity (80).…”

Section: Liver Macrophages In Metabolic Inflammationmentioning

confidence: 99%

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

et al. 2020

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Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.

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Section: Liver Macrophages In Metabolic Inflammationmentioning

confidence: 99%

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

et al. 2020

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“…GLP-2 has been shown to stimulate mesenteric blood flow in humans (Bremholm et al, 2010(Bremholm et al, , 2011Høyerup et al, 2013) and animals (Guan et al, 2003(Guan et al, , 2006Deniz et al, 2007), which may involve nitric oxide (NO) signaling (Guan et al, 2003;Hsieh et al, 2015). Recently, we have examined lipid mobilization by GLP-2 in healthy humans with or without a NOS inhibitor L-NGmonomethyl arginine acetate (L-NMMA) (Xiao et al, 2019b). GLP-2 administration after 7 h of fat ingestion increased TG in plasma, in triglyceride-rich lipoprotein (TRL), and mostly in CM, and increased blood flow in the superior mesenteric artery.…”

Section: Oral Glucose and Glp-2 As Stimuli Of Intestinal Lipid Mobilimentioning

confidence: 99%

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

et al. 2020

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Intestinal handling of dietary triglycerides has important implications for health and disease. Following digestion in the intestinal lumen, absorption, and re-esterification of fatty acids and monoacylglycerols in intestinal enterocytes, triglycerides are packaged into lipoprotein particles (chylomicrons) for secretion or into cytoplasmic lipid droplets for transient or more prolonged storage. Despite the recognition of prolonged retention of triglycerides in the post-absorptive phase and subsequent release from the intestine in chylomicron particles, the underlying regulatory mechanisms remain poorly understood. Chylomicron secretion involves multiple steps, including intracellular assembly and postassembly transport through cellular organelles, the lamina propria, and the mesenteric lymphatics before being released into the circulation. Contrary to the long-held view that the intestinal lymphatic vasculature acts mainly as a passive conduit, it is increasingly recognized to play an active and regulatory role in the rate of chylomicron release into the circulation. Here, we review the latest advances in understanding the role of lymphatics in intestinal lipid handling and chylomicron secretion. We highlight emerging evidence that oral glucose and the gut hormone glucagon-like peptide-2 mobilize retained enteral lipid by differing mechanisms to promote the secretion of chylomicrons via glucose possibly by mobilizing cytoplasmic lipid droplets and via glucagon-like peptide-2 possibly by targeting post-enterocyte secretory mechanisms. We discuss other potential regulatory factors that are the focus of ongoing and future research. Regulation of lymphatic pumping and function is emerging as an area of great interest in our understanding of the integrated absorption of dietary fat and chylomicron secretion and potential implications for whole-body metabolic health.

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“…Exogenous GLP‐2 is known to increase postprandial plasma TG levels in humans, mice, and hamsters, through enhanced chylomicron secretion 20,30‐31,34,39,40 . The increased lipid absorption in mice given GLP‐2 has been shown to require CD36 20 .…”

Section: Discussionmentioning

confidence: 99%

“…It has previously been shown that insulin‐like growth factor‐1 (IGF‐1) and the intestinal epithelial insulin‐like growth factor‐1 receptor (IE‐IGF‐1R) are required for GLP‐2‐induced increases in intestinal growth and proliferation, while the IE‐IGF‐1R has also been shown to be essential for the stimulatory effects of GLP‐2 on barrier function and microvillus length 24‐29 . Furthermore, although nitric oxide mediates the GLP‐2‐induced increase in CM production in hamsters, this does not appear to be the case in humans 30,31 . However, a role for the IE‐IGF‐1R in GLP‐2‐induced fat uptake has not been tested.…”

Section: Introductionmentioning

confidence: 99%

Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

et al. 2020

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Abbreviations: APO, apolipoprotein; CD36, cluster-of-differentiation 36; DFTT, duodenal fat tolerance test; FATP-4, fatty acid transfer protein-4; h(GLY 2 ) GLP-2, human glycine 2 -glucagon-like peptide-2; IE-IGF-1R, intestinal epithelial-insulin-like growth factor-1 receptor; KO, knockout; MTP, microsomal triglyceride transfer protein; OFTT, oral fat tolerance test; WD, Western diet. AbstractThe intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances the enterocyte chylomicron production. However, GLP-2 is known to require the intestinal-epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) for its other actions to increase intestinal growth and barrier function. The role of the IE-IGF-1R in enterocyte lipid handling was thus tested in the GLP-2 signaling pathway, as well as in response to a Western diet (WD). IE-IGF-1R knockout (KO) and control mice were treated for 11 days with h(GLY 2 )GLP-2 or fed a WD for 18 weeks followed by a duodenal fat tolerance test with C 14 -labeled triolein. Human Caco-2BBE cells were treated with an IGF-1R antagonist or signaling inhibitors to determine triglyceride-associated protein expression. The IE-IGF-1R was required for GLP-2-induced increases in CD36 and FATP-4 in chow-fed mice, and for expression in vitro; FATP-4 also required PI3K/Akt. Although WD-fed IE-IGF-1R KO mice demonstrated normal CD36 expression, the protein was incorrectly localized 2h post-duodenal fat administration.IE-IGF-1R KO also prevented the WD-induced increase in MTP and decrease in APOC3, increased jejunal mucosal C 14 -fat accumulation, and elevated plasma triglyceride and C 14 -fat levels. Collectively, these studies elucidate new roles for the IE-IGF-1R in enterocyte lipid handling, under basal conditions and in response to GLP-2 and WD-feeding.

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Glucagon‐like peptide‐2 mobilizes lipids from the intestine by a systemic nitric oxide‐independent mechanism

Cited by 14 publications

References 38 publications

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

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