High serum neurotensin level in obese adolescents is not associated with metabolic parameters, hyperphagia or food preference

Objectives Obesity is often the result of a high-calorie and unbalanced diet for a long time and can sometimes be associated with hyperphagia and eating disorders. Neurotensin (NT) is an anorexigenic peptide, which is secreted from the central nervous system and intestines, and increases intestinal fat absorption. In the literature, conflicting results regarding serum NT level in obesity and the relation of NT with metabolic parameters were reported. Besides, there is no data regarding the relation of NT with eating disorders or food preference in obese individuals. We aimed to evaluate the relation of serum NT level with metabolic parameters, hyperphagia, binge eating disorder (BED) and food preference in obese adolescents. Methods The study included 65 obese adolescents and 65 healthy controls. Anthropometric measurements, biochemical analyzes and body fat analyzes were performed in all cases. Hyperphagia score, presence of BED and three-day food intake records were also evaluated. Results NT level was significantly higher in obese adolescents than in controls and it was not associated with metabolic parameters, hyperphagia or food preference. In the obese group, NT level was not significantly different according to the presence of BED. Conclusions Serum NT level is high in obese adolescents; however, it is not associated with metabolic parameters, hyperphagia, BED or food preference.

Gut microbial structural variations as determinants of human bile acid metabolism

Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host-gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but how the highly variable genomes of gut bacteria interact with host BA metabolism remains largely unknown. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two Dutch cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete subspecies showed correlations with BA metabolism. Metagenome-wide association analysis identified 797 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the first large-scale microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.

Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after standardized oral intake of both saturated and unsaturated fat

Background In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown. Aim To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals. Setting/ methods Twenty-two healthy subjects were given 150 mL of full milk cream (54 g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 h (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides. Results An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12–31) pmol/L (P < 0.001) and at 3 h for triglycerides of 0.60 (0.43–0.78) mmol/L (P < 0.001). Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46–78) pmol/L (P < 0.001) and plasma triglycerides at 3 h of 0.32 (0.18–0.45) mmol/L (P < 0.001). The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r = 0.49, P = 0.021) and olive oil (r = 0.55, P = 0.008), respectively. Conclusion Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.

Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after a standardized oral intake of both saturated and unsaturated fats

Background: In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown.Aim: To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals.Setting/ Methods: Twenty-two healthy subjects were given 150 mL of full milk cream (54g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 hours (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides.Results: An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12-31) pmol/L (P<0.001) and at 3 h for triglycerides of 0.60 (0.43-0.78) mmol/L (P<0.001). Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46-78) pmol/L (P<0.001) and plasma triglycerides at 3 h of 0.32 (0.18-0.45) mmol/L (P<0.001). The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r=0.49, P=0.021) and olive oil (r=0.55, P=0.008), respectively.Conclusion: Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.

Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after a standardized oral intake of both saturated and unsaturated fats

Background: In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown. Aim: To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals. Setting/ Methods: Twenty-two healthy subjects were given 150 mL of full milk cream (54g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 hours (h) and at 1h, 2h and 4h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides. Results: An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12-31) pmol/L (P<0.001) and at 3 h for triglycerides of 0.60 (0.43-0.78) mmol/L (P<0.001). Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46-78) pmol/L (P<0.001) and plasma triglycerides at 3 h of 0.32 (0.18-0.45) mmol/L (P<0.001). The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r=0.49, P=0.021 ) and olive oil (r=0.55, P=0.008 ), respectively. Conclusion: Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.

Computational approaches for the discovery of natural pancreatic lipase inhibitors as antiobesity agents

Obesity is becoming one of the greatest threats to global health in the 21st century and therefore the development of novel antiobesity drugs is one of the top priorities of global drug research. An important treatment strategy includes the reduction of intestinal fat absorption through the inhibition of pancreatic lipase (PL). Natural products provide a vast pool of PL inhibitors with novel scaffolds that can possibly be developed into clinical products. Computational drug design methods have become increasingly invaluable in the drug discovery process. In recent years, the discovery of new antiobesity PL inhibitors has been facilitated by the application of computational methods. This review highlights some computer-aided drug design techniques utilized in the discovery of natural PL inhibitors.

Short-chain Fatty Acids, 4-phenylbutyric Acid and R-α-lipoic Acid, Downregulate mTORC1-dependent Intestinal Fat Absorption (P08-115-19)

Objectives Knowing that (i) high-fat diets upregulate inflammatory biomarkers in the small intestine and activate the mechanistic target of rapamycin complex 1 (mTORC1, a conserved protein kinase) and (ii) mTORC1 drives hepatic VLDL secretion, we investigated the role of intestinal mTORC1 in fat absorption and the lipid-regulating properties of 4-phenylbutyric acid (PBA) and R-α-lipoic acid (LA) in relation to mTORC1. Methods Lentivirus shRNA-based gene editing was utilized to create three stable Caco-2 cell lines that exhibit low, normal or high mTORC1 activity. Fat absorption was investigated in differentiated stable Caco-2 cells grown with oleate/albumin in Transwell permeable inserts. Results Genetic ablation of mTORC1 revealed that mTORC1 is required for the production and secretion of apoB-containing chylomicrons in Caco-2 cells. Rapamycin, an inhibitor of mTORC1, confirmed this finding as it lowered the secretion of apoB48 (−75%) and apoB100 (−47%) (P < 0.05). mTORC1 deletion was accompanied by the downregulation of APOB (−87%), MTTP (−94%), FASN (−76%), DGAT1 (−77%) and DGAT2 (−81%) genes (all P < 0.05); lower cellular abundance of apoB100 (−89%), MTTP (−63%) and FASN (−80%) (all P < 0.05); and lower media abundance of apoB48 (−66%), apoB100 (−51%) and triacylglycerols (−69%) (all P < 0.05). In Caco-2 cells harboring high mTORC1 activity, PBA or LA decreased the amounts of secreted apoB48 (−58% or −22%, respectively), apoB100 (−54% or −43%), and triacylglycerols (−46% or −38%), and the gene expression of APOB (−48% or −33%), MTTP (−54% or −31%), SREBF1 (−39% or −37%), FASN (−84% or −38%), and DGAT2 (−76% or −47%) (all P < 0.05). Conclusions A functional intestinal mTORC1 is indispensable for chylomicron production. Intake of short-chain fatty acid, PBA or LA, may be useful to prevent chylomicron overproduction-associated hypertriglyceridemia and postprandial inflammation. Funding Sources USDA Hatch Act, USDA-AFRI.