A complex role for adipose tissue macrophages

1. A complex role for adipose tissue macrophages

2. Introduction • The worldwide epidemic of obesity and type 2 diabetes mellitus has focused a great deal of attention on the physiological mechanisms regulating energy deposition and storage • Compelling evidence has accrued to suggest that both genetic and dietary forms of rodent and human obesity are accompanied by low-grade inflammation in the adipose tissue and liver • Moreover, in many instances, the generation of such an inflammatory response could represent a key link between obesity and sustained insulin resistance

3. Introduction • Proinflammatory adipose tissue macrophages (ATMs) infiltrate the adipose tissue during the late stages of obesity • The role of ATMs - including why these cells are recruited to adipose tissue in the first place and what role they might have in normal physiology - has remained a mystery • Now, a report by Xu and colleagues suggests that ATMs regulate nutrient mobilization and accessibility and so function as accessories to adipocytes

4. Findings • The findings by Xu et al. has moved the field forward by suggesting that ATMs could take up lipids into lysosomal compartments through a programme of increased lysosome biogenesis • In the context of both genetic and diet-induced obesity, Xu et al. demonstrated increased lysosomal gene expression and lipid storage within the lysosomes of ATMs. • Furthermore, their data indicate that this ability is inherent to macrophages that differentiate in the presence of adipose tissue, a process increased by obesity

5. What is the purpose of lipid uptake by ATMs? • It seems unlikely that ATMs with their modest capacity to store lipids are able to relieve an appreciable proportion of the burden suffered by stressed adipocytes in the obese state • However, ATMs might contribute either directly or indirectly to lipid trafficking in the adipose tissue • Xu et al. demonstrate that short-term inhibition of lysosomal lipid processing by chloroquine reduces basal rates of lipolysis in adipose tissue, and propose that ATMs buffer the release of lipids into the circulation by one of two possible mechanisms

6. What is the purpose of lipid uptake by ATMs? • On the one hand, lysosomal lipid accumulation by ATMs might cause the release of antilipolytic factors that act as signals in a feedback loop to the adipocytes • Alternatively, ATMs could contribute to the basal lipolytic rate by directly releasing nonesterified fatty acids, in effect recycling scavenged lipids into the circulation • This second possibility is enticing, as it indicates that ATMs could convert potentially toxic excess lipids into metabolically accessible lipids, thereby conserving nutrients & maintaining the obese state

7. Recycling of lipids by ATMs How ATMs might recycle lipids A dead or dying adipocyte (indicated by dashed line) is surrounded by ATMs, which contain scavenged lipids (yellow) in their lysosomes. These lipids are reintroduced into the circulation and can be taken up by other adipocytes

8. What is the purpose of lipid uptake by ATMs? • Although the lysosome has typically been considered to be an organelle dedicated to degradation, some research has revealed that lysosomes also contribute to recycling of metabolites • Further evidence for the potential importance of the lysosome in lipid recycling comes from lysosomal storage diseases and their associated metabolic phenotypes • Lysosomal storage diseases are characterized by the accumulation of lysosomes owing to an inability to process metabolites within these structures

9. Nutrient sequestration during lysosome dysfunction In the context of lysosomal storage diseases, scavenged lipids cannot be released into the circulation and accumulate within the lysosomes of ATMs. Consequently, adipocyte lipid content is reduced & progressive loss of adipose tissue occurs

10. Future Implications • All five mouse models of lysosomal storage disease exhibit adipose storage deficiency, whereby the inaccessibility of lipids within the lysosomal compartment results in a negative energy balance and progressive loss of the adipose tissue • These observations indicate that lipid recycling through ATM-associated lysosomes might contribute substantially to nutrient accessibility and is indispensible for maintaining adipose-tissue mass in the obese state

11. Conclusion • In the current ‘obesogenic’ environment of chronic overnutrition, the presence of insulin resistance and excess serum lipids results in metabolic disease, morbidity & mortality • Careful investigation of the roles of ATMs is, therefore, warranted to gain a clear picture of how macrophages respond to obesity, the balance of their detrimental and beneficial effects, as well as the signals from adipocytes that promote lipid processing by the lysosome