Does Cell Mechanics in Adipogenesis Offer New Keys for the Prevention and Management of Obesity?

According to the World Health Organization, >200,000,000 men and nearly 300,000,000 women (>10% of the world’s adult population) were obese in 2008. More than 40,000,000 children under the age of five were overweight in 2011. Obesity and overweight is the fifth leading risk for global death and contributes substantially to the burden of other noncommunicable diseases including diabetes (44%), ischemic heart disease (23%), and certain cancers (7–41%). Obesity affects not only high-income countries but also, increasingly, low- and middle-income countries. In these countries, children are particularly susceptible to inadequate high-fat and high-sugar nutrition that combined with low levels of physical activity leads to a rapid increase in childhood obesity. The effectiveness of the individual responsibility for management and prevention of obesity relies on the availability of affordable healthier dietary choices and means for physical activity—the provision of which, along with the support of individuals, falls within the societal responsibility of governments and public and private stake holders (1).

Obesity is characterized by an increased amount of adipose tissue in the major subcutaneous, dermal, and intraperitoneal depots of the adipose organ (2). Over the last 10 years, there has been increasing appreciation of the potential role of mechanotransduction and mechanosensitive pathways in adipogenesis and the dynamics of lipid storage in adipocytes. Findings indicate that dynamic stretch inhibits adipogenesis and the accumulation of intracellular lipid droplets through downregulation of the adipogenic transcription factors PPARγ, C/EBPα, and AP2 and an increase in β-catenin activity (3–5). Static stretch, however, stimulates adipogenesis by activating the MEK signaling pathway (6). Compressive forces inhibit adipogenesis and accumulation of intracellular lipid droplets (through downregulation of PPARγ1, PPARγ2, C/EBPα, and APN) irrespective of whether the loading is static or dynamic (7,8).

This research has focused on the effect of external forces in adipogenesis, whereas mechanotransduction may additionally be influenced by changes in the cellular and intracellular mechanics of adipocytes. Shoham et al. (9) investigated whether the mechanical properties of adipocytes change during adipogenesis, i.e., differentiation and maturation, with the associated accumulation of intracellular lipid droplets. Based on atomic force microscopy measurements on adipocytes 11 and 19 days after induction of differentiation of mouse embryonic preadipocytes (3T3-L1), Shoham et al. report that the apparent shear stiffness of the lipid droplets does not change with increasing droplet size; is 83% of the stiffness of the nucleus; and is between 2.5- and 8.3-fold the stiffness of the cytoplasm. Numerical simulations with adipocyte models representing maturation time points of between 8 and 23 days agree well with the experimental results. Considering the intracellular accumulation of lipid such that eventually most of the cytoplasm is occupied by one or a few large lipid droplets combined with the higher stiffness of the lipid droplets compared to the cytoplasm, it is evident that the whole-cell stiffness of adipocytes increases during adipogenesis. A second focus of the study is the intracellular motility of the lipid droplets. Interferometric phase microscopy experiments and corresponding finite-element models show that lipid droplets, which are constrained through cytoskeletal structures, mechanically deform their intracellular environment and induce shear strains of up to 50% in a cytoplasmic boundary layer around the lipid droplets.

In combination with existing knowledge and ongoing research, e.g., on the biophysics and biology of intracellular lipid droplets (10), the findings on the cell mechanics and changes thereof during adipocyte maturation by Shoham et al. (9) should serve as point of departure for further inquiry into mechanical interactions between adipocytes and their extracellular environment. Such interactions are likely to induce or alter mechanosensitive signaling pathways and lead to cascades of mechanobiological adaptations at the cell and tissue levels. An improved understanding of the mechanobiological mechanisms involved in adipogenesis and adipocyte dysfunction may offer new approaches for the prevention and treatment of obesity and overweight—and with this, provide opportunities for the biophysical research community to contribute to fulfilling the imperative societal responsibility described by the World Health Organization.