Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats

Abstract

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB) and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including GLUT-1, GLUTT-4, pAS160, AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups while the Exe-9 and Glp-1r KD were opposite. Known to activate insulin signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice

“…The findings suggest that lipids reduce the release of enteric hormones, accelerating glucose transit (or vice versa), and that cryptal function may be regulated by glucose exposure, both in the duodenum and in the colon. Interestingly, the exclusion of GI walls from food transit (e.g., following bariatric surgery [ 13 , 15 ]) or the use of drugs reducing motility (e.g., GLP1 receptor agonists [ 15 , 16 , 31 ]) result in an elevation in adipose tissue [ 13 , 16 ] or brain [ 15 , 31 ] GU. In our study, the co-administration of glucose and lipids caused an intermediate situation, with fast transit and low incretin levels, likely balancing brain effects, while stimulating adipose tissue GU.…”

“…In addition, the administration of a single glucose or standard meal, passing through the GI tract, has been associated with systemic and liver inflammation [ 11 , 12 ], though it remains to be established whether these effects require specifically the GI entry route. Accumulating evidence from, e.g., bariatric surgery [ 13 , 14 , 15 ] or drugs affecting GI function (GLP1 agonists [ 15 , 16 ], metformin [ 17 , 18 , 19 , 20 ]), point to the GI tract as an important regulator of tissue glucose uptake (GU).…”

The ABA/LANCL Hormone/Receptor System in the Control of Glycemia, of Cardiomyocyte Energy Metabolism, and in Neuroprotection: A New Ally in the Treatment of Diabetes Mellitus?

“…It is a great challenge of modern societies to devise efficient strategies to prevent and treat neurodegeneration in the elderly. LANCL1 and LANCL2 are both highly expressed in the central nervous system (CNS) [ 19 ], where the glucose transporters comprise GLUT1 and GLUT4 [ 50 , 51 ], both targets of LANCL1/2-mediated increased expression. A role for LANCL1/2 in protection from neuroinflammation, particularly from its oxidation-mediated damage, could be hypothesized from the fact that both proteins bind to reduced glutathione (GSH) and have an SH3-binding domain [ 52 ].…”

Brain Imaging of the GLP-1 Receptor in Obesity Using 68Ga-NODAGA-Exendin-4 PET

“…In a recent study, we demonstrated the ability of 68 Ga-NODAGA-exendin-4 to visualize GLP-1 receptor expression on pancreatic beta cells [ 31 ]. Since GLP-1 receptor agonists are successfully used to reduce body weight and improve insulin resistance in obese subjects, and bariatric surgery may influence GLP-1 levels [ 32 ], we recently started a clinical study on the effects of bariatric surgery on GLP-1 binding as measured with 68 Ga-NODAGA-exendin-4 PET.…”