de Wet Group

Metabolism and ABC Transporters

The de Wet laboratory has a long-standing focus on the ATP-binding cassette (ABC) superfamily of transporters.  ABC transporters play essential roles in cellular physiology by mediating the ATP-dependent transport of a wide range of molecules across biological membranes.  My interest in ABC transporters began during my doctoral training, working on multi-drug resistant ABC transporters, and was further developed during my post-doctoral research on ABCC8 or SUR1.

Within this superfamily, a central focus of my current research has been ABCC5 (also known as MRP5).  ABCC5 was historically considered an “orphan” transporter, as its physiological function was poorly defined compared with well-characterised family members such as CFTR (ABCC7) or classical multidrug-resistance proteins.  Through a combination of genetic, physiological, and metabolic approaches, my laboratory has provided evidence that ABCC5 plays an important role in energy homeostasis.

Using CRISPR-mediated deletion of Abcc5 in mice, we demonstrated that Abcc5-deficient animals are leaner, more insulin-sensitive, and more physically active than wild-type controls.  These mice also display increased circulating levels of gut-derived hormones, including glucagon-like peptide-1 (GLP-1).  Together, these findings indicate a shift toward a metabolically healthier and more responsive endocrine state.

In addition to its metabolic roles, my group has contributed to broader characterisation of ABCC5 function, with studies implicating this transporter in memory consolidation, circadian rhythm regulation, and glutamatergic signalling in the brain. While these processes are not all directly linked to metabolism, they highlight the diverse physiological functions of this transporter.

 See here for a recent review:

1. Chinoy, J.; Meller, C.; de Wet, H. An Emerging Paradigm for ABCC5/MRP5 Function in Human Physiology. Int. J. Mol. Sci. 2025, Sept 26, 9211. https://doi.org/10.3390/ijms2618

Regulation of Gut Hormone Release

A major theme of my recent research is understanding how gut endocrine cells sense nutrients and regulate hormone secretion, particularly within the small intestine. Enteroendocrine K-cells and L-cells release peptide hormones such as glucose-dependent insulinotropic peptide (GIP) and GLP-1 in response to nutrient ingestion.  These hormones play critical roles in insulin secretion, appetite regulation, and overall metabolic homeostasis.

My laboratory aims to identify molecular mechanisms that link nutrient sensing to hormone secretion, with a particular emphasis on the role of ABC transporters in these processes. We investigate how changes in transporter expression or activity influence gut hormone release and, consequently, systemic metabolic responses.

The work on ABCC5 provides a clear example of this approach, demonstrating that altered transporter function enhances GLP-1 secretion.  These findings have important implications for understanding the pathophysiology of obesity and type 2 diabetes, and for identifying new therapeutic targets.

In parallel, we study how environmental and cellular factors - such as extracellular pH or NMDA receptor activation - modulate hormone secretion from enteroendocrine L-cells.  We are also interested in nutritional interventions, including the metabolic effects of ketone ester consumption via the regulation of gut hormones such as ghrelin, GLP-1 and GDF15, as highlighted in recent work examining their impact on appetite regulation and metabolic health.

Systemic Effects of Oxytocin on Metabolism and Gut Hormones

Although oxytocin is not a primary focus of my laboratory, my research programme includes work that links gut hormone signalling with central endocrine pathways involved in energy balance.  In collaborative studies with colleagues in Japan, Professors Shimomura and Maejima, we have explored interactions between oxytocin and incretin hormones GLP-1 and GIP in the regulation of metabolism.

In one key study, we demonstrated that low-dose systemic oxytocin, when co-administered with GLP-1, leads to reduced food intake and body weight in mice.  These findings suggest a synergistic interaction between oxytocin signalling and incretin pathways in the control of energy homeostasis.

This work aligns with a growing body of evidence indicating that oxytocin—traditionally associated with parturition and social behaviour—also acts as a modulator of feeding behaviour and metabolic regulation through interactions with hypothalamic and gut hormone circuits.

In particular, we have also examined the metabolic effects of traditional Japanese herbal medicines, such as Kamikihito (KKT), known to activate oxytocin receptors.  These studies explore how complex herbal formulations influence gut–brain endocrine pathways, providing additional insight into integrative and translational approaches to metabolic regulation.