Tamer Coskun, Eli Lilly, United States
Tamer Coskun，礼来公司，美国

Simon M. Luckman,  西蒙·拉克曼，
The University of Manchester, United Kingdom
英国曼彻斯特大学
Luiza Ghila, University of Bergen, Norway
Luiza Ghila，挪威卑尔根大学

Frank Reimann  弗兰克·雷曼
$◻$$◻$◻\square fr222@cam.ac.uk
Fiona Mary Gribble  菲奥娜·玛丽·格里布尔

James-Okoro P-P, Lewis JE, Gribble FM and Reimann F (2025) The role of GIPR in food intake control.
James-Okoro PP、Lewis JE、Gribble FM 和 Reimann F （2025） GIPR 在食物摄入控制中的作用。
Front. Endocrinol. 16:1532076.
前面。内分泌醇。16:1532076.
doi: 10.3389/fendo.2025.1532076
土井：10.3389/fendo.2025.1532076

© 2025 James-Okoro, Lewis, Gribble and Reimann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
© 2025 詹姆斯-奥科罗、刘易斯、格里布尔和雷曼。这是一篇根据知识共享署名许可 （CC BY） 条款分发的开放获取文章。允许在其他论坛上使用、分发或复制，前提是注明原作者和版权所有者，并根据公认的学术惯例引用本期刊的原始出版物。不允许使用、分发或复制不符合这些条款的内容。

Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretin hormones playing key roles in the control of food intake, nutrient assimilation, insulin secretion and whole-body metabolism. Recent pharmacological advances and clinical trials show that unimolecular co-agonists that target the receptors for the incretins - GIP and glucagon-like peptide 1 (GLP-1) - offer more effective treatment strategies for obesity and type 2 diabetes mellitus (T2D) compared with GLP-1 receptor (GLP1R) agonists alone, suggesting previously underappreciated roles of GIP in regulating food intake and body weight. The mechanisms by which GIP regulates energy balance remain controversial as both agonism and antagonism of the GIP receptor (GIPR) produce weight loss and improve metabolic outcomes in preclinical models. Recent studies have shown that GIPR signalling in the central nervous system (CNS), especially in regions of the brain that regulate energy balance, is essential for its action on appetite regulation. This finding has sparked interest in understanding the mechanisms by which GIP engages brain circuits to reduce food intake and body weight. In this review, we present key knowledge around the actions of GIP on food intake regulation and the potential mechanisms by which GIPR and GIPR/GLP1R agonists may regulate energy balance.
葡萄糖依赖性促胰岛素多肽 （GIP） 是两种肠促胰岛素激素之一，在控制食物摄入、营养吸收、胰岛素分泌和全身代谢方面发挥关键作用。最近的药理学进展和临床试验表明，靶向肠促胰岛素受体的单分子辅激动剂 - GIP 和胰高血糖素样肽 1 （GLP-1） - 为肥胖和 2 型糖尿病 （T2D） 提供更有效的治疗策略与单独使用 GLP-1 受体 （GLP1R） 激动剂相比，这表明 GIP 以前被低估在调节食物摄入量和体重方面的作用。GIP 调节能量平衡的机制仍然存在争议，因为在临床前模型中，GIP 受体 （GIPR） 的激动作用和拮抗作用都会减轻体重并改善代谢结果。最近的研究表明，中枢神经系统 （CNS） 中的 GIPR 信号传导，特别是在调节能量平衡的大脑区域，对于其对食欲调节的作用至关重要。这一发现引发了人们对了解 GIP 参与大脑回路以减少食物摄入量和体重的机制的兴趣。在这篇综述中，我们介绍了有关 GIP 对食物摄入调节的作用以及 GIPR 和 GIPR/GLP1R 激动剂调节能量平衡的潜在机制的关键知识。

Glucose-dependent insulinotropic polypeptide (GIP)/GIP-receptor (GIPR), Glucagonlike peptide-1 receptor (GLP1R), food intake, body weight, central nervous system, obesity, diabetes
葡萄糖依赖性促胰岛素多肽 （GIP）/GIP 受体 （GIPR）、胰高血糖素样肽 1 受体 （GLP1R）、食物摄入量、体重、中枢神经系统、肥胖、糖尿病

Glucose-dependent insulinotropic polypeptide (previously known as gastric inhibitory peptide, GIP) is a gut-derived hormone produced and secreted from enteroendocrine K cells of the duodenum and upper jejunum upon meal ingestion (1). Along with glucagonlike peptide-1 (GLP-1), GIP plays a key role in regulating postprandial blood sugar levels through what is known as the incretin effect - where an estimated $50-70\mathrm{\%}$$50-70\mathrm{\%}$50-70%50-70 \% of insulin release in response to a meal is mediated by GIP and GLP-1 (1). As the insulinotropic effect of GIP is diminished in patients with type 2 diabetes (T2D) (2), the therapeutic potential of the GIP axis has been relatively underexplored, whilst structurally optimised agonists of GLP-1 receptors (GLP1R) have been developed and introduced for the treatment of T2D and obesity. Focus is now turning to the therapeutic potential of targeting GIP receptors
葡萄糖依赖性促胰岛素多肽（以前称为胃抑制肽，GIP）是一种肠道来源的激素，在进餐时由十二指肠和上空肠的肠内分泌 K 细胞产生和分泌 （1）。与胰高血糖素样肽-1 （GLP-1） 一起，GIP 通过所谓的肠促胰岛素效应在调节餐后血糖水平方面发挥着关键作用，即 GIP 和 GLP-1 介导的进餐反应胰岛素释放的估计 $50-70\mathrm{\%}$$50-70\mathrm{\%}$50-70%50-70 \% 值 （1）。由于 GIP 在 2 型糖尿病 （T2D） 患者中的促胰岛素作用减弱 （2），GIP 轴的治疗潜力一直相对不足，而结构优化的 GLP-1 受体 （GLP1R） 激动剂已被开发和引入用于治疗 T2D 和肥胖症。现在的焦点转向靶向 GIP 受体的治疗潜力
(GIPR), in light of the preclinical and clinical success of agents combining a GLP1R agonist with either a GIPR agonist or antagonist - strategies that deliver superior body weight reduction compared with GLP1R agonists alone (3-8).
（GIPR），鉴于将 GLP1R 激动剂与 GIPR 激动剂或拮抗剂联合使用的药物在临床前和临床上取得了成功——与单独使用 GLP1R 激动剂相比，这些策略可实现卓越的体重减轻 （3-8）。

Although research into the effects of GIP on appetite regulation is advancing, significant gaps remain in our understanding of the specific mechanisms underlying its anorectic action, particularly within the brain. Clarifying these central mechanisms is crucial, as the brain plays a vital role in regulating energy balance, and understanding how GIP affects central pathways to modulate food intake will be invaluable for improving GIP-based therapies for obesity and diabetes treatment. In this review, we present current knowledge on the role of GIPR signalling in the control of energy balance and examine emerging evidence regarding the potential mechanisms by which GIP affects food intake.
尽管对 GIP 对食欲调节影响的研究正在取得进展，但我们对其厌食作用背后的具体机制的理解仍然存在重大差距，尤其是在大脑内。阐明这些中枢机制至关重要，因为大脑在调节能量平衡方面起着至关重要的作用，了解 GIP 如何影响调节食物摄入的中枢通路对于改进基于 GIP 的肥胖和糖尿病治疗疗法将非常宝贵。在这篇综述中，我们介绍了有关 GIPR 信号传导在控制能量平衡中的作用的当前知识，并检查了有关 GIP 影响食物摄入的潜在机制的新证据。

The mature form of GIP, GIP(1-42), is a 42 -amino acid hormone derived from posttranslational processing of the 153amino acid precursor, pre-pro-GIP, through prohormone convertase (PC) 1/3-dependent cleavage after Arg-65 in the proGIP sequence (9). GIP belongs to the secretin/glucagon family of structurally related neuroregulatory peptides, which also includes pituitary adenylate cyclase-activating peptide (PACAP) and growth hormone-releasing hormone (GHRH). Its amino acid sequence is highly conserved across species, showing over $90\mathrm{\%}$$90\mathrm{\%}$90%90 \% sequence identity across human, murine, porcine and bovine species (1). GIP(1-42) is susceptible to rapid degradation and inactivation by dipeptidyl peptidase 4 (DPP4), the same enzyme that inactivates GLP-1, resulting in a short plasma half-life of 5-7 minutes (10).
GIP 的成熟形式 GIP（1-42） 是一种 42 个氨基酸的激素，来源于 153 个氨基酸前体 pre-gip 的翻译后加工，通过 proGIP 序列中 Arg-65 后激素原转化酶 （PC） 1/3 依赖性裂解 （9）。GIP 属于结构相关神经调节肽的促胰液素/胰高血糖素家族，其中还包括垂体腺苷酸环化酶激活肽（PACAP）和生长激素释放激素（GHRH）。其氨基酸序列在物种之间高度保守，在人类、小鼠、猪和牛物种中显示出过度 $90\mathrm{\%}$$90\mathrm{\%}$90%90 \% 序列同一性 （1）。GIP（1-42）容易受到二肽基肽酶 4（DPP4）的快速降解和失活，二肽基肽酶 4（DPP4 与使 GLP-1 失活的酶相同），导致血浆半衰期短，为 5-7 分钟（10）。

GIP is primarily produced by enteroendocrine K cells in the upper small intestinal epithelium $(11,12)$$(11,12)$(11,12)(11,12). A shorter form, GIP(130 ), has been reported in $\alpha$$\alpha$alpha\alpha-cells of pancreatic islets by immunohistochemistry, reverse-transcription polymerase chain reaction (RT-PCR), and in situ hybridisation (ISH) (13). In contrast, we were unable to detect GIP-peptides by mass spectrometry in human or mouse islets, or Gip-mRNA in FACSpurified islet cell types from mice raised in our facility $(14,15)$$(14,15)$(14,15)(14,15).
GIP 主要由上小肠上皮的肠内分泌 K 细胞产生 $(11,12)$$(11,12)$(11,12)(11,12) 。一种较短的形式 GIP（130） 已通过免疫组织化学、逆转录聚合酶链反应 （RT-PCR） 和原位杂交 （ISH） 在胰岛细胞中 $\alpha$$\alpha$alpha\alpha 报道 （13）。相比之下，我们无法通过质谱法检测人或小鼠胰岛中的 GIP-肽，也无法检测我们设施中饲养的小鼠的 FACS 纯化胰岛细胞类型中的 Gip-mRNA $(14,15)$$(14,15)$(14,15)(14,15) 。

The Gipr gene, while primarily known for its expression in pancreatic $\beta$$\beta$beta\beta-cells, is also found in other tissues, including adipose tissue, stomach, bone, adrenal cortex, heart, pituitary, endothelial cells, testis and several brain regions (1). Activation of GIPR thus exerts pleiotropic biological effects including neuroprotection (16), decreased bone resorption (17), and improved lipid metabolism and storage (18).
Gipr 基因虽然主要以其在胰腺 $\beta$$\beta$beta\beta 细胞中的表达而闻名，但也存在于其他组织中，包括脂肪组织、胃、骨骼、肾上腺皮质、心脏、垂体、内皮细胞、睾丸和几个大脑区域 （1）。因此，GIPR 的激活发挥多效性生物学效应，包括神经保护 （16）、骨吸收减少 （17） 以及改善脂质代谢和储存 （18）。

GIP was not historically considered to have any direct action on the brain, but intracerebroventricular (ICV) injection of high concentrations of GIP affected the secretion of anterior pituitary
GIP 历来不被认为对大脑有任何直接作用，但脑室内 （ICV） 注射高浓度 GIP 会影响垂体前叶的分泌
hormones including follicle-stimulating hormone (FSH) and growth hormone (GH), leading to the hypothesis that GIP could act on its receptors in hypothalamic regions near the third ventricle (19), and marking the first indication that GIP could have a regulatory role in the central nervous system (CNS). Subsequently, GIP receptors were identified in a rat cerebral cortex cDNA library and found to be similar to the receptors for glucagon and GLP-1, placing GIPR in the vasoactive intestinal polypeptide (VIP)/glucagon/secretin receptor superfamily (class B1) of seven transmembrane-domain G-protein coupled receptors (GPCRs) (20). GIP receptors primarily signal through Gos/adenylyl cyclase activation, which increases intracellular cAMP levels; in pancreatic $\beta$$\beta$beta\beta-cells, this activates protein kinase A (PKA) and exchange protein activated by cAMP2 (EPAC2), resulting in a downstream increase in intracellular calcium levels and exocytosis of insulin (21-23).
包括促卵泡激素 （FSH） 和生长激素 （GH） 在内的激素，导致假设 GIP 可以作用于第三脑室附近下丘脑区域的受体 （19），并标志着 GIP 可能在中枢神经系统 （CNS） 中发挥调节作用的第一个迹象。随后，在大鼠大脑皮层 cDNA 文库中鉴定出 GIP 受体，发现与胰高血糖素和 GLP-1 受体相似，将 GIPR 置于血管活性肠多肽 （VIP）/胰高血糖素/促胰液素受体超家族（B1 类）七个跨膜结构域 G 蛋白偶联受体 （GPCR） （20）。GIP 受体主要通过 Gos/腺苷酸环化酶激活发出信号，从而增加细胞内 cAMP 水平;在胰腺 $\beta$$\beta$beta\beta 细胞中，这会激活蛋白激酶 A （PKA） 和由 cAMP2 （EPAC2） 激活的交换蛋白，导致细胞内钙水平的下游增加和胰岛素的胞吐作用 （21-23）。

Initial exploration of Gipr mRNA expression in the rat brain employing ISH and RT-qPCR revealed its wide distribution across many areas including the olfactory bulb, cerebral cortex, hippocampus, mammillary bodies, anterior and lateral septum, cortical amygdala, substantia nigra, thalamic nuclei, rostral raphe nuclei, choroid plexus, cuneate nucleus, cerebellum and brainstem $(21,24)$$(21,24)$(21,24)(21,24). In a study by Kaplan et al., autoradiographic localisation of saturable (25) GIP radioligand binding identified GIP binding sites in discrete areas of the rat brain, including the cortex, subiculum, anterior olfactory nucleus, inferior colliculus, lateral septal nucleus and the inferior olive (26). More recently, Adriaenssens et al. employed a Gipr-Cre knock-in mouse model, in which Giprexpressing cells exhibit expression of a fluorescent EYFP reporter, to map Gipr expression in the mouse CNS (27). Immunostaining for EYFP highlighted Gipr expression in regions such as the medial preoptic area, subfornical organ, anterodorsal thalamic nucleus, magnocellular preoptic nucleus, suprachiasmatic nucleus and the interfascicular nucleus - alongside areas already identified in previous studies. Results from Cre-reporter lines must be interpreted with caution, as they can report cells expressing only very low levels of the receptor message, and might aberrantly report lineage tracing of cells that transiently expressed Cre-recombinase during development. Knock-in of Cre-recombinase into the native Gipr-locus, as in this model, should however reduce the risk of aberrant expression. Notably, Gipr mRNA expression was confirmed by qPCR in mouse hypothalamus and by ISH (RNAscope) specifically in the arcuate nucleus (ARH) and dorsomedial nucleus (DMH) of the hypothalamus of mice and several nuclei of the hypothalamus of humans (27). ISH (RNAscope) also confirmed expression of Gipr in the area postrema (AP) and nucleus tractus solitarius (NTS) of the brainstem in mice $(28,29)$$(28,29)$(28,29)(28,29) and Cynomolgus monkey (29). In the hindbrain, the signal in the AP was more pronounced compared to the NTS, suggesting that this area might be a particularly critical brain region for the regulation of energy balance and/or food intake regulation in response to GIPR-agonists.
利用 ISH 和 RT-qPCR 对 Gipr mRNA 在大鼠脑中的表达进行初步探索，发现其广泛分布于嗅球、大脑皮层、海马体、体、前隔和外隔、皮质杏仁核、黑质、丘脑核、喙中缝核、脉络丛、楔形核、小脑和脑干 $(21,24)$$(21,24)$(21,24)(21,24) .在 Kaplan 等人的一项研究中，可饱和 （25） GIP 放射配体结合的放射自显影定位确定了大鼠大脑离散区域的 GIP 结合位点，包括皮层、下沟、前嗅核、下丘、外间隔核和下橄榄 （26）。最近，Adriaenssens 等人采用 Gipr-Cre 敲入小鼠模型，其中表达 Gipr 的细胞表现出荧光 EYFP 报告基因的表达，以绘制小鼠中枢神经系统中的 Gipr 表达图谱（27）。EYFP 的免疫染色突出了 Gipr 在内侧视前区、穹窿下器官、丘脑前核、大细胞视前核、视交叉上核和束间核等区域的表达，以及先前研究中已经确定的区域。必须谨慎解释 Cre 报告基因系的结果，因为它们可以报告仅表达非常低水平的受体信息的细胞，并且可能会异常报告在发育过程中瞬时表达 Cre 重组酶的细胞的谱系追踪。然而，如本模型所示，将 Cre 重组酶敲入天然 Gipr 基因座应该会降低异常表达的风险。 值得注意的是，Gipr mRNA 表达通过小鼠下丘脑的 qPCR 和 ISH （RNAscope） 得到证实，特别是在小鼠下丘脑的弓状核 （ARH） 和背内侧核 （DMH） 以及人类下丘脑的几个核中 （27）。ISH （RNAscope） 还证实了 Gipr 在小鼠 $(28,29)$$(28,29)$(28,29)(28,29) 和食蟹猴脑干的 postrema （AP） 和孤束核 （NTS） 区域的表达 （29）。在后脑中，与 NTS 相比，AP 中的信号更为明显，这表明该区域可能是调节能量平衡和/或食物摄入调节以响应 GIPR 激动剂的特别关键的大脑区域。

Transcriptomic profiling using single-cell RNA sequencing of fluorescent cells isolated from Gipr-Cre mice further revealed heterogeneous expression of Gipr across neuronal and non-
使用从 Gipr-Cre 小鼠分离的荧光细胞的单细胞 RNA 测序进行转录组学分析，进一步揭示了 Gipr 在神经元和非神经元中的异质表达
neuronal cell types in the hypothalamus. Based on the expression of cell-type-specific marker genes, Gipr was identified in mural cells, ependymocytes, pericytes, vascular and leptomeningeal cells (VLMCs), smooth muscle cells (SMCs), endothelial cells (ECs), oligodendrocytes (OLs), and neurons (27, 30). Analysis of the neuronal cluster showed Gipr expression in both glutamatergic and GABAergic neurons, along with co-expression of neurohormones involved in energy balance, including Sst, Avp, Pthlh, and fewer neurons expressing Cartpt and Tac1 (27). More recently active $GIPR$$GIPR$GIPRG I P R expression in mouse and human hypothalamus was confirmed by single-nucleus (sn) RNA sequencing and spatial transcriptomics (31). Gipr neurons expressed receptors for key gut peptides known to regulate energy homeostasis such as ghrelin and cholecystokinin (CCK), and calcium imaging analysis demonstrated that stimulating these receptors excites Gipr cells, suggesting that Gipr neurons can respond to food-related signals from the periphery.
下丘脑中的神经元细胞类型。基于细胞类型特异性标记基因的表达，在壁细胞、室管膜细胞、周细胞、血管和软脑膜细胞 （VLMC）、平滑肌细胞 （SMC）、内皮细胞 （EC）、少突胶质细胞 （OL） 和神经元中鉴定出 Gipr （27， 30）。对神经元簇的分析显示，Gipr 在谷氨酸能和 GABA 能神经元中均有表达，以及参与能量平衡的神经激素的共表达，包括 Sst、Avp、Pthlh，以及表达 Cartpt 和 Tac1 的较少神经元 （27）。最近，通过单核 （sn） RNA 测序和空间转录组学证实了小鼠和人下丘脑中的活性 $GIPR$$GIPR$GIPRG I P R 表达 （31）。Gipr 神经元表达已知调节能量稳态的关键肠道肽的受体，例如生长素释放肽和胆囊收缩素 （CCK），钙成像分析表明，刺激这些受体会激发 Gipr 细胞，表明 Gipr 神经元可以对来自外周的食物相关信号做出反应。

Histological and snRNAseq have characterised Gipr expression in the brainstem, revealing differential expression of Gipr within the NTS and AP (27, 32-34). Gipr expression is abundant in inhibitory GABAergic neurons within the AP, but less so in the NTS and the nodose ganglia of the vagus nerve (28, 35). Projections from inhibitory GABAergic neurons are mostly confined within the AP itself with minimal projections to the proximal NTS (32). Some studies additionally identified Gipr in a small population of glutamatergic neurons in the dorsal vagal complex (DVC) of the mouse brainstem (28), potentially reflecting the sparse Gipr-positive cells in the NTS that were also identifiable by RNAscope. Both GABAergic and glutamatergic Gipr-positive neurons were identified in snRNAseq analyses of the combined AP and NTS from rats and mice $(36,37)$$(36,37)$(36,37)(36,37). Non-neuronal cells, particularly OLs and a few astrocytes express Gipr (33, 34, 37), revealing the multifaceted nature of Gipr distribution in the brainstem, as in hypothalamus, as outlined above.
组织学和 snRNAseq 表征了 Gipr 在脑干中的表达，揭示了 Gipr 在 NTS 和 AP 中的差异表达 （27， 32-34）。Gipr 在 AP 内的抑制性 GABA 能神经元中大量表达，但在 NTS 和迷走神经结节中表达较少 （28， 35）。来自抑制性 GABA 能神经元的投射大多局限于 AP 本身，对近端 NTS 的投射极少 （32）。一些研究还在小鼠脑干背侧迷走神经复合体 （DVC） 的一小群谷氨酸能神经元中发现了 Gipr （28），这可能反映了 NTS 中稀疏的 Gipr 阳性细胞，这些细胞也可以通过 RNAscope 识别。在大鼠和小鼠联合 AP 和 NTS 的 snRNAseq 分析中鉴定出 GABA 能和谷氨酸能 Gipr 阳性神经元 $(36,37)$$(36,37)$(36,37)(36,37) 。非神经元细胞，特别是 OL 和一些星形胶质细胞表达 Gipr （33， 34， 37），揭示了 Gipr 在脑干中分布的多方面性质，如上所述，在下丘脑中。

The expression of Gipr and identification of GIP binding sites in the brain, particularly in regions protected by the blood-brain barrier (BBB), suggests that GIP potentially plays a physiological role in the CNS. This raises important questions about whether central Gipr-expressing populations respond to circulating GIP from the periphery or if there is a central population of GIPproducing cells. Early studies, which attempted to detect Gip mRNA in the rat brain by northern blot hybridisation, ISH and RT-PCR were unable to detect any Gip mRNA (21, 38, 39). Given this, GIP was suggested to enter the brain through circumventricular organs (CVO) such as the AP and act on other brain regions (21). Alternatively, it was suggested that another ligand might activate GIPR within the brain (21). Some studies, however, have reported GIP mRNA and protein in rat retina (40), hippocampus (41), olfactory bulb, cerebellar Purkinje cells, cerebral cortex, substantia nigra (24, 42), and striatum (43), with moderate expression in the amygdala, lateral septal nucleus, pretectal nuclei, thalamic reticular
Gipr 的表达和大脑中 GIP 结合位点的鉴定，特别是在受血脑屏障 （BBB） 保护的区域，表明 GIP 可能在中枢神经系统中发挥生理作用。这提出了一个重要问题，即表达 Gipr 的中枢群体是否对来自外围的循环 GIP 做出反应，或者是否存在产生 GIP 的细胞的中心群体。早期研究试图通过北方印迹杂交、ISH 和 RT-PCR 检测大鼠大脑中的 Gip mRNA，但无法检测到任何 Gip mRNA （21， 38， 39）。鉴于此，建议 GIP 通过脑室周围器官 （CVO） （例如 AP） 进入大脑并作用于其他大脑区域 （21）。或者，有人建议另一种配体可能会激活大脑内的 GIPR （21）。然而，一些研究报道了大鼠视网膜 （40）、海马体 （41）、嗅球、小脑浦肯野细胞、大脑皮层、黑质 （24， 42） 和纹状体 （43） 中的 GIP mRNA 和蛋白质，在杏仁核、外间隔核、顶盖前核、丘脑网状中等表达
nucleus as well as in several nuclei in the thalamus, hypothalamus, and brainstem $(24,42)$$(24,42)$(24,42)(24,42). In these studies, GIP immunoreactivity and mRNA colocalised with the neuronal marker NeuN, but not the glial marker GFAP $(24,42)$$(24,42)$(24,42)(24,42), suggesting that Gip-expressing cells may be neuronal. However, efforts by our research group using a Gip-Cre-reporter model that readily labels Gip-expressing cells in the duodenum (44) have been unable to detect Gip expression in the brain (45, 46). Given these findings, there is ongoing debate about whether GIP is truly produced in the brain or if its central effects are mediated by circulating GIP arriving from the periphery, or if an alternative ligand engages central GIPRs. It is plausible that GIP produced by the gut might affect brain function, as peripherally injected GIP was detected in cerebrospinal fluid (CSF) collected from mice cisterna magna (47). The questions of whether GIP is produced centrally and the physiological role of GIPR located behind the BBB continue to be subjects of active investigation.
细胞核以及丘脑、下丘脑和脑干的几个细胞核 $(24,42)$$(24,42)$(24,42)(24,42) 。在这些研究中，GIP 免疫反应性和 mRNA 与神经元标志物 NeuN 共定位，但与神经胶质标志物 GFAP 不共定位 $(24,42)$$(24,42)$(24,42)(24,42) ，表明表达 Gip 的细胞可能是神经元的。然而，我们的研究小组使用易于标记十二指肠中表达 Gip 的细胞的 Gip-Cre 报告器模型 （44） 的努力无法检测到大脑中的 Gip 表达 （45， 46）。鉴于这些发现，关于 GIP 是否真正在大脑中产生，或者其中枢效应是否是由来自外周的循环 GIP 介导的，或者替代配体是否与中枢 GIPR 结合，一直存在争论。肠道产生的 GIP 可能会影响大脑功能，因为在从小鼠大池收集的脑脊液 （CSF） 中检测到外周注射的 GIP （47）。GIP 是否集中产生以及位于 BBB 后面的 GIPR 的生理作用仍然是积极研究的主题。

Hormones released from the gut postprandially play key roles in regulating energy balance by modulating appetite and blood glucose levels (48), making them viable targets for the treatment of obesity and T2D. Among these, GLP-1 has gained significant attention for its ability to decrease body weight by inhibiting food intake, regulate glucose metabolism and improve renal and cardiovascular function $(49,50)$$(49,50)$(49,50)(49,50). This led to the development of GLP-1-based cardiometabolic medicines including liraglutide and semaglutide, which have shown clinical success in treating obesity (51-53). However, the use of GLP-1-based drugs comes with dosedependent adverse effects, with up to $60\mathrm{\%}$$60\mathrm{\%}$60%60 \% of patients reporting gastrointestinal (GI)-related issues. Furthermore, many patients struggle to reach their glycaemic and weight loss targets (54). This has spurred efforts to identify and develop agents that can enhance and complement GLP1R agonism.
餐后肠道释放的激素通过调节食欲和血糖水平在调节能量平衡方面发挥着关键作用 （48），使其成为治疗肥胖和 T2D 的可行靶点。其中，GLP-1 因其通过抑制食物摄入、调节糖代谢和改善肾脏和心血管功能 $(49,50)$$(49,50)$(49,50)(49,50) 来减轻体重的能力而受到广泛关注。这导致了基于 GLP-1 的心脏代谢药物的开发，包括利拉鲁肽和索马鲁肽，这些药物在治疗肥胖方面显示出临床成功 （51-53）。然而，使用基于 GLP-1 的药物会带来剂量依赖性不良反应，多达 $60\mathrm{\%}$$60\mathrm{\%}$60%60 \% 一些患者报告胃肠道 （GI） 相关问题。此外，许多患者难以达到血糖和减肥目标 （54）。这刺激了识别和开发可以增强和补充 GLP1R 激动作用的药物的努力。

An innovative approach in recent drug development is the design of unimolecular peptides that engage multiple receptors to improve therapeutic efficacy. Combining GLP1R agonists with activity against receptors for other hormones such as GIP, glucagon and amylin has shown promising results ( $3,4,55,56$$3,4,55,56$3,4,55,563,4,55,56 ). The approach stems from findings that co-treatment with GIPR and GLP1R agonists enhanced weight loss in diet-induced obese (DIO) mice (3, 4). Unimolecular GLP1R/GIPR dual agonists not only amplify the metabolic benefits of GLP-1 therapies but may also reduce common side effects, offering an effective strategy for managing obesity and T2D-related conditions (57, 58).
最近药物开发中的一种创新方法是设计单分子肽，该肽与多种受体结合以提高治疗效果。将 GLP1R 激动剂与针对 GIP、胰高血糖素和淀粉样蛋白等其他激素受体的活性相结合已显示出有希望的结果 （ $3,4,55,56$$3,4,55,56$3,4,55,563,4,55,56 ）。该方法源于与 GIPR 和 GLP1R 激动剂联合治疗可增强饮食诱导的肥胖 （DIO） 小鼠的体重减轻的发现 （3， 4）。单分子 GLP1R/GIPR 双重激动剂不仅可以放大 GLP-1 疗法的代谢益处，还可以减少常见的副作用，为管理肥胖和 T2D 相关疾病提供有效的策略 （57， 58）。

The first dual GLP1R/GIPR agonist, MAR709 (also known as NNC0090-2746) showed balanced in vitro activity at GIPR ( ${\mathrm{EC}}_{50}=$${\mathrm{EC}}_{50}=$EC_(50)=\mathrm{EC}_{50}= 3 pM ) and GLP1R ( ${\mathrm{EC}}_{50}=5\mathrm{pM}$${\mathrm{EC}}_{50}=5\mathrm{pM}$EC_(50)=5pM\mathrm{EC}_{50}=5 \mathrm{pM} ) (3). In rodent models with genetic and diet-induced obesity, MAR709 produced greater weight loss and glycaemic improvements compared with pharmacokinetically matched GLP-1 treatments (3). In a phase 2 b trial, the reductions in body weight and blood glucose in T2D patients treated with MAR709 at the single tested dose were similar to dose-titrated
第一种双重 GLP1R/GIPR 激动剂 MAR709（也称为 NNC0090-2746）在 GIPR （ ${\mathrm{EC}}_{50}=$${\mathrm{EC}}_{50}=$EC_(50)=\mathrm{EC}_{50}= 3 pM） 和 GLP1R （ ${\mathrm{EC}}_{50}=5\mathrm{pM}$${\mathrm{EC}}_{50}=5\mathrm{pM}$EC_(50)=5pM\mathrm{EC}_{50}=5 \mathrm{pM} ） 处显示出平衡的体外活性 （3）。在遗传和饮食诱发的肥胖啮齿动物模型中，与药代动力学匹配的 GLP-1 治疗相比，MAR709 产生了更大的体重减轻和血糖改善 （3）。在一项 2 b 期试验中，在单次测试剂量下接受 MAR709 治疗的 T2D 患者体重和血糖的降低与剂量滴定相似