Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats

Hankir, Mohammed K.; Seyfried, Florian; Hintschich, Constantin; Diep, Thi Ai; Kleberg, Karen; Kranz, Mathias; Deuther‐Conrad, Winnie; Téllez, Luis A.; Rullmann, Michael; Patt, Marianne; Teichert, Jens; Hesse, Swen; Sabri, Osama; Brust, Peter; Hansen, Harald S.; Araújo, Ivan E. de; Krügel, Ute; Fenske, Wiebke

doi:10.1016/j.cmet.2016.12.006

Cited by 108 publications

(99 citation statements)

References 54 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exaggerated secretion of gut peptides, such as GLP‐1 and PYY, following meal ingestion , reduced appetite for dietary lipids, and decreased sensitivity to the hedonic properties of palatable food were observed in RYGB surgery‐treated patients. These changes have also been reported in rodent models and are considered to contribute to the beneficial effects of RYGB surgery; however, the precise mechanism remains unknown. In the current study, we revealed that CpdB modulated gut peptide release and HFD intake vaguely similar to the RYGB surgery.…”

Section: Discussionmentioning

confidence: 89%

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

et al. 2020

View full text Add to dashboard Cite

Monoacylglycerol O‐acyltransferase 2 (MGAT2) is one of the key enzymes responsible for triglyceride (TG) re‐synthesis in the small intestine. We have previously demonstrated that pharmacological inhibition of MGAT2 has beneficial effects on obesity and metabolic disorders in mice. Here, we further investigate the effects of MGAT2 inhibition on (a) fat‐induced gut peptide release and fat intake in normal mice and (b) metabolic disorders in high‐fat diet (HFD)‐fed ob/ob mice, a model of severe obesity and type 2 diabetes mellitus, using an orally bioavailable MGAT2 inhibitor Compound B (CpdB). CpdB inhibited elevation of plasma TG in mice challenged with an oil‐supplemented liquid meal. Oil challenge stimulated the secretion of two gut anorectic hormones (peptide tyrosine–tyrosine and glucagon‐like peptide‐1) into the bloodstream, and these responses were augmented in mice pretreated with CpdB. In a two‐choice test using an HFD and a low‐fat diet, CpdB selectively inhibited intake of the HFD in normal mice. Administration of CpdB to HFD‐fed ob/ob mice for 5 weeks suppressed food intake and body weight gain and inhibited elevation of glycated hemoglobin. These results indicate that pharmacological MGAT2 inhibition modulates fat‐induced gut peptide release and fat intake in normal mice and improves obesity and diabetes in HFD‐fed ob/ob mice and thus may have potential for development into a treatment of obesity and its related metabolic diseases.

show abstract

Section: Discussionmentioning

confidence: 89%

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

et al. 2020

View full text Add to dashboard Cite

show abstract

“…It has been previously shown that OEA is linked to dopamine activity in the striatum (Tellez et al, ) which is necessary for normal feeding behavior (Sotak, Hnasko, Robinson, Kremer, & Palmiter, ). Increased OEA synthesis has been observed following RYGB (Hankir et al, ). In contrast, OEA levels have been shown to be decreased in obese subjects (Artmann et al, ; Igarashi, DiPatrizio, Narayanaswami, & Piomelli, ).…”

Section: Discussionmentioning

confidence: 99%

Roux‐en‐Y gastric bypass surgery normalizes dopamine D1, D2, and DAT levels

Hamilton

Swenson²,

Hajnal

et al. 2018

Synapse

View full text Add to dashboard Cite

Roux-en-Y gastric bypass surgery (RYGB) is one of the most effective treatments for morbid obesity. However, increased substance abuse following RYGB has been observed clinically. This study examined the effects of RYGB on the dopamine system to elucidate these observed changes in reward-related behavior. Rats were assigned to four groups: normal diet with sham surgery, ad libitum high fat (HF) diet with sham surgery, restricted HF diet with sham surgery, and HF diet with RYGB surgery. Following surgeries, rats were kept on their respective diets for 9 weeks before they were sacrificed. [ H]SCH 23390, [ H]Spiperone, and [ H]WIN35 428 autoradiography was performed to quantify the effects of diet and RYGB surgery on dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter (DAT) binding. Rats on a chronic HF diet became obese with reduced D1R-like binding within the ventrolateral striatum and the nucleus accumbens core, reduced D2R-like binding in all areas of the striatum and nucleus accumbens core and shell, and reduced DAT binding in the dorsomedial striatum. Restricted HF diet rats showed similar reductions in D1R-like and D2-R-like binding as the obese rats, and reduced DAT binding within all areas of the striatum. Both RYGB and restricted HF diet rats showed similar weight reductions, with RYGB rats showing no difference in binding compared to controls. The observed changes in binding between non-treated obese rats and RYGB rats demonstrates that HF dietary effects on the dopamine system were reversed by RYGB.

show abstract

“…2013; Hankir et al. 2017). The proposed mechanism involves a nongenomic effect of the PPAR α receptor activation, which would activate protein kinases responsible for the phosphorylation status of the nicotinic acetylcholine receptors (nAChRs) modifying the response of dopaminergic neurons to nicotine (Melis et al.…”

Section: Discussionmentioning

confidence: 99%

Oleoylethanolamide-induced anorexia in rats is associated with locomotor impairment

et al. 2018

View full text Add to dashboard Cite

The endogenous peroxisome proliferator‐activated receptor alpha (PPAR‐α) agonist Oleoylethanolamide (OEA) inhibits eating in rodents, mainly by delaying the onset of meals. The underlying mechanisms of OEA‐induced anorexia, however, remain unclear. Animals treated with high OEA doses were shown to display signs of discomfort and impaired locomotion. Therefore, we first examined whether the impaired locomotion may contribute to OEA's anorectic effect. Second, it is controversial whether abdominal vagal afferents are necessary for OEA's anorectic effect. Thus, we explored alternative peripheral neural pathways mediating IP OEA's anorectic effect by performing a celiac‐superior mesenteric ganglionectomy (CGX) or a subdiaphragmatic vagal deafferentation (SDA) alone or in combination. Exogenously administered OEA at a commonly used dose (10 mg/kg BW, IP) concurrently reduced food intake and compromised locomotor activity. Attempts to dissociate both phenomena using the dopamine D2/D3 receptor agonist Quinpirole (1 mg/kg BW, SC) failed because Quinpirole antagonized both, OEA‐induced locomotor impairment and delay in eating onset. CGX attenuated the prolongation of the latency to eat by IP OEA, but neither SDA nor CGX prevented IP OEA‐induced locomotor impairment. Our results indicate that IP OEA's anorectic effect may be secondary to impaired locomotion rather than due to physiological satiety. They further confirm that vagal afferents do not mediate exogenous OEA's anorectic effects, but suggest a role for spinal afferents in addition to an alternative, nonneuronal signaling route.

show abstract

Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats

Cited by 108 publications

References 54 publications

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

Roux‐en‐Y gastric bypass surgery normalizes dopamine D1, D2, and DAT levels

Oleoylethanolamide-induced anorexia in rats is associated with locomotor impairment

Contact Info

Product

Resources

About