Peripheral serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor in males.

Postprandial dyslipidemia is commonly present in people with type II diabetes and obesity and is characterized by overproduction of apolipoproteinB48 (apoB48)-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity, however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and i.p. poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins (TRLs). Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TRL particles, resulting in lower plasma TG and apoB48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, ind---icating that serotonin controls dietary fat absorption and chylomicron secretion via 5HT4 receptor.

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