Microgravity as a translational model for metabolic dysfunction: implications for obesity, insulin resistance,...

The long-term effects of physical inactivity, whether due to microgravity in spaceflight or an inactive lifestyle on Earth, can lead to a range of metabolic problems. This review examines the physiological response to reduced gravity and contemporary inactivity, with a focus on obesity, insulin resistance, type 2 diabetes, and hepatic and pancreatic steatosis, all of which are associated with metabolic dysfunction (MASLD, MASPD).

A narrative review approach was used, integrating evidence from spaceflight research, bed rest studies, and clinical trial data to examine the metabolic consequences of reduced mechanical loading and physical inactivity.

Available evidence suggests that mechanical load deprivation alters fat distribution, promotes visceral adiposity, and initiates inflammation and immune-metabolic reprogramming. Emerging countermeasures, such as vibration platforms, resistive suits, and omics-directed personalized therapies, have been explored as potential strategies to mitigate these changes. A 12-week cascade model is proposed to illustrate the disease progression of metabolic dysfunction under reduced mechanical loading.

This review has brought together aerospace physiology and metabolic medicine, highlighting microgravity as a translational model that helps improve our understanding and mitigate lifestyle-induced metabolic disorders on Earth.

A comprehensive literature search was performed using electronic databases, including PubMed/MEDLINE, Scopus, and Web of Science. The search strategy incorporated a combination of the following keywords: Microgravity, Sedentary lifestyle, Insulin resistance, Ectopic fat, Metabolic syndrome, Steatotic Liver, and Pancreatic Diseases. Studies were selected based on relevance to the topic and included human studies (astronaut data, clinical cohorts, and bed rest trials), animal models of simulated microgravity, and in vitro mechanical studies. Articles not directly related to metabolic and endocrine outcomes of mechanical unloading were excluded. Given the heterogeneity of study designs and outcomes, findings were synthesized using a structured narrative approach.