Background
Alterations in lipid and cholesterol metabolism are major risk factors for the development of cardiovascular disease (CVD) in patients with obesity and type-2 diabetes (T2D). Albeit best known for its ability to enhance glucose-stimulated insulin secretion, the glucose-dependent insulinotropic polypeptide (GIP) also stimulates white adipose tissue (WAT) lipid disposal and reduces inflammation in the brain and WAT [
1]. Unimolecular co-agonists at the receptors for GIP and the glucagon-like peptide-1 (GLP-1) are among the most promising drugs in clinical development for the treatment of obesity and diabetes [
2]. Notably, GLP-1/GIP co-agonists not only reduce body weight and improve glucose metabolism with greater efficacy relative to GLP-1 receptor (GLP-1R) agonism in preclinical [
3] and clinical studies [
2], but also outperform GLP-1R monotherapy in reducing triglyceride and cholesterol levels [
4]. However, the therapeutic effect of GIP receptor (GIPR) agonism to treat dyslipidemia and reduce CVD-risk is not well defined yet and thus subject of intense ongoing investigations. Particularly, it warrants clarification whether GIP may even improve lipid metabolism independent of its ability to reduce obesity and hyperglycemia.
GIP is secreted from enteroendocrine K-cells especially in response to dietary lipids and glucose. The biological function of GIP to potentiate glucose-dependent beta cell insulin secretion (incretin effect) is well established [for review see
5]. GIP’s extra-pancreatic actions are less known and especially its pro- or anti-obesogenic effects are controversially discussed [
6]. In brief, GIP might have an indirect role in atherosclerosis, via the regulation of macrophage-driven inflammation and foam cell formation, vascular smooth muscle cell proliferation and arterial remodelling. However, it has also been shown that increased plasma levels of GIP are associated with atherosclerosis in humans [
7]. Recent success of GIP as add-on therapy to glucagon-like peptide 1 (GLP-1) in unimolecular dual incretins to glucose and body weight improvements in pre-clinical and clinical studies indicate GIP-dependent contributions [
3,
8,
9]. In line with this notion, a long-acting fatty acylated GIP (acyl-GIP) was recently shown to decrease body weight and food intake by acting on the CNS GIPR [
10]. And while the GIPR:GLP-1R co-agonist MAR709 decreased body weight with superior potency over a pharmacokinetically-matched GLP-1 control in wildtype mice, the superiority of MAR709 over GLP-1 vanished in mice with neuronal loss of GIPR [
10]. In addition, GLP-1/GIP co-agonists lowered fasting cholesterol and triglyceride levels more efficiently than comparable benchmarked GLP-1 mono-agonist treatments in phase 2 clinical trials with T2D patients [
8,
9].
Comprised of anatomically distinct depots, white adipose tissue is essential for lipid deposition. Fat accumulation in subcutaneous fat harbors little to no risk to develop metabolic complications, whereas expansion of visceral depots predisposes to the metabolic syndrome [
11]. In WAT, GIPR is expressed in macrophages, pericytes endothelial and mesothelial cells. GIPR signaling enhances fat tissue blood flow, lipoprotein lipase activity, insulin action, glucose and fatty acid uptake, de novo lipogenesis and lipolysis. GIP also modulates macrophage-dependent inflammation in WAT [
6].
The pharmacological potential of GIPR mono-agonism to improve systemic lipid metabolism and to reduce CVD-risk has not been fully explored yet. Particularly, it is unclear whether GIP reduces hypercholesterolemia and atherosclerotic plaque formation independent of its ability to decrease body weight and hyperglycemia. Herein we tested whether a body weight neutral dose of a previously published long acting acylated GIP analog (acyl-GIP) improves dyslipidemia and atherogenesis in male LDL receptor knock out (LDLR-/-) mice.
Discussion
Herein we identified an unanticipated efficacy of chronic acyl-GIP administration to improve dyslipidemia and CVD in a western diet-induced mouse model of atherosclerosis independently of body weight loss, indicating a specific acyl-GIP-induced effect within the treatment spectrum of clinically advancing novel poly-pharmacological approaches for obesity and T2D. These findings might initiate future studies to explore the potential of GIP mono- or poly-pharmacology to treat disturbances of lipid metabolism, which contributes to reduced cardiovascular mortality.
Although GLP-1/GIP co-agonists are one of the most promising drugs to treat obesity and diabetes and have been shown to reduce fasting cholesterol and triglycerides in T2D patients [
8,
9], GIP-dependent contributions to metabolic benefits achieved with this combinatorial therapy remain unclear. GIP plays a physiologic role in the disposition of ingested fat by stimulating lipid uptake in subcutaneous adipose tissue [
17‐
21]. This effect is pronounced in lean individuals and blunted in obese and T2D subjects [
22]. Moreover, high fasting plasma GIP levels were associated with low plasma LDL cholesterol in both, men and women, and low plasma triglycerides in women at risk for developing T2D [
17]. These associations were independent of fasting plasma insulin levels. Taking into account the fact that the herein observed acyl-GIP-induced improvement of dyslipidemia in LDLR-/- mice was also independent of changes in plasma insulin levels points to a direct effect of acyl-GIP on adipocyte metabolism. In addition, our findings that chronic acyl-GIP treatment predominately targeted subcutaneous fat and to a lesser extent visceral fat in male LDLR-/- mice suggests a fat depot preference of our GIP-agonist. Of note, our RNAseq analysis indicated that pathways such as the complement and coagulation cascade or fibrinolysis were significantly down regulated by acyl-GIP compared to vehicle treatment in western diet fed male LDLR-/- mice. These findings are of interest as alterations in the hemostatic system are associated with WAT dysfunction and the prothrombotic state observed in obesity [
23] and thus may suggest an ulterior acyl-GIP-mediated effect in adipose tissue. It should be mentioned at this point that higher fasting GIP levels have been reported in correlation with an unhealthy fat distribution as indicated by a higher visceral to subcutaneous fat distribution exclusively in men, but not women [
17]. Thus, potential sex-specific differences of GIP action on visceral and subcutaneous adipose tissue physiology warrants further examination.
Interestingly, there is evidence in the literature that body weight loss by caloric restriction re-sensitized obese individuals to GIP action in subcutaneous fat [
24]. Hence, one can assume that GLP-1/GIP mediated weight loss could actually prime GIP action to improve dyslipidemia.
It is very difficult to assess GIPR receptor occupancy by acyl-GIP, also because it would be different based on which tissue is under examination. The herein used acyl-GIP requires 60–100 nmol/kg to affect body weight and food intake in diet induced obese rodents [
10]. Thus, the applied dose of 10 nmol/kg was hence clearly subthreshold to affect body weight, food intake and also glycemia. Together with the known effect of GIP to regulate lipid metabolism in adipocytes [
25] our findings might initiate future studies to explore the potential of GIP mono- or poly-pharmacology to treat disturbances of lipid metabolism and potentially reducing cardiovascular mortality. It is important here to state that our findings have been observed in a rodent model for cardio-metabolic disease and thus it is impossible at this point to extrapolate to humans without further investigations. It is important to note that disorders in triglyceride and cholesterol metabolism are major risk factors for the development of lethal atherosclerotic cardiovascular complications in obese individuals and T2D patients. Besides body weight and glucose management, this is particularly relevant in light of the recent consensus in the field that the growing prevalence of cardio-metabolic disease will perhaps be the greatest health challenge throughout the world and that therefore multifaceted interventions and treatments in a new era of precision medicine will be required to provide the best possible comprehensive care for patients with cardiometabolic disease [
26‐
28].
We just recently showed that Tirzepatide is only a weak and partial agonist at the mouse GIPR with a 75-fold less potency at the mouse relative to human GIPR [
29]. Based on these findings it seems plausible that Tirzepatide is not suitable to assess the mode of action of GIPR agonism and GIPR:GLP-1R co-agonism in mice and was hence omitted herein.
Regarding future obesity treatment strategies implementing novel GIP/GPL-1 co-agonists that are emerging it is unclear whether every co-agonist will be as beneficial as and superior to single GLP-1R agonism. For example, the metabolic effect of NNC0090-2746 relative to liraglutide has been tested at a single dose for only 12-wks of treatment [
8]. This study design seems suboptimal in many different aspects due to the lack of multiple higher doses which are crucial for e.g. Tirzepatide to maximize weight loss. In addition, the study duration of 12 wks may not have been long enough in light of the SURPASS trials showing that much longer treatment durations are required to see the maximal effects on weight loss and improvement in glucose control.
Acknowledgements
We thank Luisa Müller, Laura Sehrer, Emiljia Malogajski, Cynthia Striese, Sebastian Cucuruz, Markus Brielmeier at HMGU and Yvonne Jansen at IPEK for excellent assistance with mouse husbandry and experiments. C.W. is van der Laar-Professor of Atherosclerosis.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.