Advances in the Regulation of Glucose and Lipid Metabolism by Tryptophan and Its Metabolites

doi:10.13560/j.cnki.biotech.bull.1985.2025-1029

Abstract

Abstract:

Tryptophan (Trp) is an essential amino acid that generates a diverse array of bioactive metabolites via the kynurenine, serotonin, and indole pathways, participating extensively in physiological processes such as oxidative stress, inflammatory responses, and immune responses. Recent studies indicate that Trp metabolism serves not only as a pivotal hub maintaining host health and gut micro-ecological balance, but its dysregulation is also closely associated with the onset and progression of a spectrum of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), hyperlipidemia, and metabolic dysfunction-associated fatty liver disease (MAFLD). Trp metabolism influences disease progression by modulating glucose and lipid metabolism, insulin signal transduction, and immune homeostasis. Targeting the activity of rate-limiting enzymes in Trp metabolism—such as tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO), and kynurenine 3-monooxygenase (KMO)—can intervene in the production of key metabolites, thereby correcting metabolic imbalances, alleviating inflammation, or improving cellular function. This approach holds promise as a novel therapeutic strategy for various diseases. This review focuses on the pathophysiological functions of key Trp metabolites and systematically summarizes the organ-specific regulatory mechanisms of Trp metabolism in the liver, intestine, adipose tissue, and pancreas. It elucidates the pro-inflammatory effects and insulin resistance associated with kynurenine, the dual regulatory roles of serotonin in glucose and lipid metabolism, and highlights the capacity of gut microbiota-derived indole derivatives, such as indolepropionic acid, to alleviate metabolic disorders via anti-inflammatory, antioxidant, and gut barrier protection mechanisms. Furthermore, this article explores the inter-organ communication mechanisms where Trp metabolites act as signaling molecules to regulate hepatic lipid metabolism and inflammation via the “gut-liver axis”, and modulate appetite and energy balance via the “gut-brain axis”. These insights aim to provide a theoretical basis for the diagnosis and treatment of diseases related to glucose and lipid metabolic disorders.

Key words: tryptophan, serotonin, metabolic diseases, “gut-liver axis”

WANG Dan, HUANG Hong-jie, CAO Sui-zhong, HUANG Yi-xin. Advances in the Regulation of Glucose and Lipid Metabolism by Tryptophan and Its Metabolites[J]. Biotechnology Bulletin, 2026, 42(7): 11-21.

Figures/Tables 3

Fig. 1 Regulatory role of tryptophan metabolism in various organsTrp： Tryptophan. 5-HT： 5-Hydroxytryptamine. IAA： Indole-3-acetic acid. IALD： Indole-3-aldehyde. ILA： Indole-3-lactic acid. Ahr： Aryl hydrocarbon receptor. IL-22： Interleukin-22. TPH1： Tryptophan hydroxylase 1. TDO： Tryptophan 2，3-dioxygenase. KYN： Kynurenine. NAD⁺： Nicotinamide adenine dinucleotide. MLT： Melatonin. SREBP： Sterol regulatory element-binding protein. PPARγ： Peroxisome proliferator-activated receptor gamma. HTR2A： 5-Hydroxytryptamine receptor 2A. IDO： Indoleamine 2，3-dioxygenase. STAT3： Signal transducer and activator of transcription 3. IL-6： Interleukin-6. UCP-1： Uncoupling protein 1. HTR2C： 5-Hydroxytryptamine receptor 2C. 5-HT1F： 5-Hydroxytryptamine receptor 1F. Figure was created with BioRender

Table 1 Regulatory roles and targets of tryptophan metabolites

色氨酸代谢产物 Tryptophan metabolites	关键酶 Key enzymes	代谢物来源 Source	代谢调控作用 Metabolic regulatory function	作用靶点 Action target	参考文献 Reference
KYN	IDO	脂肪细胞	诱导肥胖和胰岛素抵抗	AhR-STAT3-IL-6	［46］
3-HK	KMO	胰岛β细胞	诱导胰岛素抵抗	-	［52］
KYNA	KAT	肝细胞	改善肝脏脂肪变性	AMPK/ORP150	［32］
NAD⁺	ACMSD	肝细胞	减轻脂肪肝	-	［30］
5-HT	TPH1	肠道嗜铬细胞	促进肠道蠕动	-	［24］
	-	产芽孢细菌	促进肠道脂质吸收	-	［8］
	TPH1	肥大细胞	诱导肝脏脂质累积	HTR2A-PPARγ	［34］
	TPH1	白色脂肪细胞	促进脂肪生成	HTR2A	［41］
	TPH1	棕色脂肪细胞	抑制脂肪分解	UCP1	［43］
	TPH1	胰岛β细胞	抑制胰岛α细胞释放胰高血糖素	5-HT1F受体	［53］
	TPH1	胰岛β细胞	抑制胰岛β细胞分泌胰岛素	HTR2C	［55］
MLT	AANAT	肝细胞	减轻肝脏脂质累积	SREBP-1c	［37］
IPA	ACD	肠道菌群	改善胰岛素敏感性，减少脂质累积	FFAR3-IL-25、NFκB	［18-19］
IAlD	-	肠道菌群	改善胰岛素敏感性，抗肥胖	AhR、Nrf2	［20］

Fig. 2 Tryptophan metabolism in inter-organ crosstalkSTAT3： Signal transducer and activator of transcription 3. HTR2C： 5-Hydroxytryptamine receptor 2C. 5-HT： 5-Hydroxytryptamine. TPH2： Tryptophan hydroxylase 2. Trp： Tryptophan. POMC Neurons： Pro-opiomelanocortin neurons. IPA： Indole-3-propionic acid. BA： Bile acids. TPH1： Tryptophan hydroxylase 1. FXR： Farnesoid X receptor. FGF15/19： Fibroblast growth factor 15/19. FGFR4： Fibroblast growth factor receptor 4. CYP7A1： Cholesterol 7 alpha-hydroxylase （Cytochrome P450 Family 7 Subfamily A Member 1）. HTR2A： 5-Hydroxytryptamine receptor 2A. HTR2B： 5-Hydroxytryptamine receptor 2B. PPARγ： Peroxisome proliferator-activated receptor gamma. Hepatocyte： Hepatocyte. Lipogenesis： Lipogenesis. Figure was created with BioRender

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