Obesity continues to be a major global health crisis. Although rates have somewhat stabilised in high income countries, there has been a sharp increase in low/middle income countries (LMIC) over the last decade. Indeed, along with the rising rates of obesity in LMIC, there is now an emergent health crisis in relation to increased incidence of gestational diabetes mellitus (GDM) (Muche et al., 2019). As with obesity during pregnancy, GDM increases the risk of developing type 2 diabetes in mothers and their offspring (Plows et al., 2018). Although obesity and GDM are interlinked issues, they are not necessarily mutually exclusive, with GDM occurring in lean women and women living with obesity. This raises the question of whether there are divergences in outcomes and pathologies in relation to the complications that occur as a result of both GDM and obesity and what may be mediating these effects? The placenta is a unique organ. It is temporary in nature, existing only during pregnancy, but is an essential mediator of maternal pregnancy adaptation and fetal development. Not only does it provide an interface between maternal/fetal systems, shuttling nutrients and oxygen to the fetus, but also it is critical for immunological adaptions in the mother that ensure that the fetus is not rejected by the maternal immune system. Despite its critical role, it is perhaps one of the least understood organs. However, we are beginning to build a picture of the role of this organ in relation to maternal health status during pregnancy. Subtle alterations in placental morphology, molecular pathways and endocrine output can have a significant effect. Indeed, there is now emerging evidence that tiny particles called extracellular vesicles shed from the placenta into the maternal circulation may contribute to the development of obstetric conditions such as pre-eclampsia and GDM (James-Allan et al., 2020). It should also be noted that obesity can also impact the development of the placenta. Obesity is associated with a state of chronic low-grade inflammation. But how does this extend to pregnancy and the placenta? Pregnancy itself is associated with a unique inflammatory profile. Indeed, inflammatory processes are critical for many aspects of pregnancy progression. For those living with obesity, entering pregnancy in an already inflamed state can exacerbate the normal physiological adaptations to pregnancy resulting in upregulation of factors such as pro-inflammatory cytokines, including tumour necrosus factor (TNF)α, interleukin (IL)-6 and IL-1β, resulting in excessive insulin resistance and knock-on effects on other organs including the placenta. This inflammatory state can impact structural, vascular and endocrine properties in the placenta that contribute to pregnancy complication and developmental effects in the offspring both in the short- and in the long-term (Howell & Powell, 2017). In this issue of The Journal of Physiology, Musa et al. (2023) explore the structural and molecular effects and interactions between obesity and GDM in the placenta of women in Cape town, South Africa. This work not only examines the interplay between obesity and GDM on placental parameters such as structure and molecular inflammatory markers, but also does so in the setting of a LMIC, something that is lacking in the current literature. They found differential effects in relation to placental structure. The percentage of stem villi are decreased with obesity in women without GDM but increased when GDM was present with obesity. The percentage of the intervillous space was increased with obesity compared to non-obesity in the absence of GDM but, where obesity and GDM occurred together, there was a decrease in the percentage of intervillous space compared to obesity alone. Syncytiotrophoblast (STB), fetal capillaries and stoma volumes, as well as theoretical diffusion capacity, were all decreased in the presence of obesity irrespective of GDM. These results clearly demonstrate that, despite obesity being the driving force behind placental structural adaptations, GDM can have differential impacts particularly in the setting of obesity. Musa et al. (2023) also demonstrate the effects of GDM and obesity on placental TNFα. Placental lysate concentrations, as well as localisation studies, demonstrated differential effects with increased STB localisation in response to obesity and decreased lysate concentrations with GDM (accompanied by decreased circulating concentrations). Although circulating, mRNA and lysate IL-6 concentrations were not altered, localisation of IL-6 showed differential effects. Women living with obesity without GDM had decreased IL-6 localisation in placental villi and, where obesity and GDM occurred together, the reduced localisation that was seen in villus stroma and fetal capillaries was more potent compared to obesity alone. These findings suggest that there is a complex interplay between obese and GDM states in relation to inflammation. It is important to note that GDM patients were receiving metformin treatment, which is known to reduce inflammation and may influence the findings. The temporal nature of placental adaptation may need to be considered in this line of research. Much work is carried out on term placentae but, when considering the impact of the placenta as a causative factor in GDM, earlier gestational ages should be assessed (although this of course is a difficult tissue to collect). Novel technologies in relation to placental extracellular vesicles and placental organoids may be options to fill this gap in knowledge. Fetal sex also represents another factor that may introduce limitations. An emerging line of research indicates that placentae from male and female fetuses can have differential patterns in terms of structure and function in response to early life stressors such as pregnancy complication and obesity. These differential effects may be important in determining tailored strategies in relation to newborn health. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. C.R. was responsible for the conception or design of the work; drafting the work or revising it critically for important intellectual content; and final approval of the version to be published. C.R. agrees to be accountable for all aspects of the work. University College Dublin (UCD): Clare Reynolds, R21075 Open access funding provided by IReL.