Summary: Group‐level obesity can be seen as an emergent property of a complex system, consisting of feedback loops between individual body weight perception, individual weight‐related behaviour and group‐level social norms (a product of group‐level ‘normal' body mass index (BMI) and sociocultural ‘ideal' BMI). As overweight becomes normal, the norm might be counteracting health awareness in shaping individual weight‐related behaviour. System dynamics modelling facilitates understanding and simulating this system's emergent behaviour. We constructed six system dynamics models (SDMs) based on an expert‐informed causal loop diagram and data from six sociocultural groups (Dutch, Moroccan and South‐Asian Surinamese men and women). The SDMs served to explore the effect of three scenarios on group‐level BMI: ‘what if' weight‐related behaviour were driven by (1) health awareness, (2) norms or (3) a combination of the two. Median BMI decreased approximately 50% and 30% less in scenarios 2 and 3, respectively, than in 1. In men, the drop in BMI was approximately two times larger in scenario 1 versus 3, whereas in women, the drop was approximately equal in these scenarios. This study indicates that the overweight norm in men holds group‐level BMI close to overweight despite health awareness. Since norms are counteracting health awareness less strongly in women, other drivers of obesity must be more relevant.

The kidneys are crucial for maintaining Mg ²⁺ homeostasis. Along the proximal tubule and thick ascending limb, Mg ²⁺ is reabsorbed paracellularly, while along the distal convoluted tubule (DCT), Mg ²⁺ is reabsorbed transcellularly via transient receptor potential melastatin 6 (TRPM6). TRPM6 and other renal transporter expressions are regulated by sex hormones. To investigate renal Mg ² handling, we have developed sex-specific computational models of electrolyte transport along rat superficial nephron. Model simulations indicated that along the proximal tubule and thick ascending limb, Mg ²⁺ and Na ⁺ transport occur parallelly, but they are dissociated along the DCT. In addition, our models predicted higher paracellular Mg ²⁺ permeability in females to attain similar cortical thick ascending limb fractional Mg ²⁺ reabsorption in both sexes. Furthermore, DCT fractional Mg ²⁺ reabsorption is higher in females than in males, allowing females to better fine-tune Mg ²⁺ excretion. We validated our models by simulating the administration of three classes of diuretics. The model predicted significantly increased, marginally increased and significantly decreased Mg ²⁺ excretions for loop, thiazide and K-sparing diuretics, respectively, aligning with experimental findings. The models can be used to conduct in silico studies on kidney adaptations to Mg ²⁺ homeostasis alterations during conditions such as pregnancy, diabetes and chronic kidney disease.

Magnesium (Mg²⁺) is crucial for several cellular and physiological processes and is tightly regulated due to health risks associated with imbalances. Mg²⁺, calcium (Ca²⁺), parathyroid hormone, and vitamin D₃ are tightly coupled, ensuring proper bone metabolism and intestinal and renal absorption of Mg²⁺ and Ca²⁺. While several Ca²⁺ homeostasis models exist, no computational model has been developed to study Mg²⁺ homeostasis. We developed a computational model of Mg²⁺ homeostasis in male rats, integrating it with an existing Ca²⁺ homeostasis model, to understand the interconnected physiological processes regulating their homeostasis. We then analyzed adaptations in these interconnected processes under (1) dietary Mg²⁺ deficiency, (2) low/high dietary Ca²⁺ with Mg²⁺ deficiency, and (3) vitamin D₃ deficiency. Model simulations predicted severe hypomagnesemia and mild hypocalcemia with significant dietary Mg²⁺ deficiency. Low dietary Ca²⁺ improved, while high dietary Ca²⁺ worsened Mg²⁺ deficiency. Finally, vitamin D₃ deficiency caused severe hypocalcemia, with minimal impact on Mg²⁺ homeostasis.

The kidney plays an important role in the maintenance of whole body Ca²⁺ balance by regulating Ca²⁺ reabsorption and excretion. This computational modeling study provides insights into how Ca²⁺ transport along the nephron is coupled to Na⁺. Model results indicated that along the proximal tubule and thick ascending limb, Ca²⁺ and Na⁺ transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.

Sex influences cardiovascular disease, and the timing of onset of acute cardiovascular events exhibits circadian rhythms. Kidney function also exhibits sex differences and circadian rhythms. How do the natriuretic and diuretic effects of diuretics, a common treatment for hypertension that targets the kidneys, differ between the sexes? And how do these effects vary during the day? To answer these questions, we conducted computer simulations to assess the effects of loop, thiazide, and K⁺-sparing diuretics.

Renal hemodynamics, renal transporter expression levels, and urine excretion exhibit circadian variations. Disruption of these diurnal patterns is associated with the pathophysiology of hypertension and chronic kidney disease. Renal hemodynamics determines oxygen delivery, whereas renal transport and metabolism determines oxygen consumption; the balance between them yields renal oxygenation which also demonstrates 24-h periodicity. Another notable modulator of kidney function is sex, which has impacts on renal hemodynamics and transport function that are regulated by as well as independent of the circadian clock. The goal of this study was to investigate the diurnal and sexual variations in renal oxygen consumption and oxygenation. For this purpose, we developed computational models of rat kidney function that represent sexual dimorphism and circadian variation in renal hemodynamics and transporter activities. Model simulations predicted substantial differences in tubular Na⁺ transport and oxygen consumption among different nephron segments. We also simulated the effect of loop diuretics, which are used in the treatment of renal hypoxia, on medullary oxygen tension. Our model predicted a significantly higher effect of loop diuretics on medullary oxygenation in female rats compared to male rats and when administered during the active phase.