Fight Aging!

Enough excess visceral fat tissue will kill you. It causes chronic inflammation that accelerates all of the common fatal age-related diseases, and further produces disarray in metabolism leading to metabolic syndrome and then type 2 diabetes. Considering that type 2 diabetes can, for the vast majority of patients, be turned back even in the later stages through a sustained low calorie diet, it is quite amazing the amount of funding present in the field chasing pharmaceutical solutions to this condition. A sizable fraction of medical researchers are working on this problem rather than others precisely because that is where the funding is. Like the rest of us, scientists need to earn a living. Looking at the situation from a glass half full perspective, this work should inform work on the interaction of aging with normal levels of fat tissue in later life, a point when fat starts to produce a number of similar problems to those exhibited by young, obese individuals.

In the recent past, researchers have made some progress on determining the mechanisms by which excess fat produces inflammation: fat cells can act in similar ways to infected cells, rousing the immune system; in addition, the debris from dying fat cells produces similar results. A sizable proportion of fat tissue in obese individuals is composed of the immune cells called macrophages, and in the research noted below, it is signaling by these immune cells that links the presence of excess fat tissue to some of the consequences of excess fat tissue. It is possible to envisage a chain of consequences involving fat dysfunction and the immune system that initially directly produces inflammation, and then the progressively larger number of immune cells that become involved in the tissue themselves cause further dysfunction in metabolic processes.

It is also worth considering the evidence for deposits of visceral fat tissue to produce harmful effects through the creation of a larger than usual level of cellular senescence. Senescent cells cause problems through altered signaling, the senescence-associated secretory phenotype. It will be interesting to see the degree to which the signaling mechanisms examined in the paper below are produced by senescent versus normal macrophage cells. This is all fairly speculative: researchers have found macrophages showing signs of senescence in older individuals, but there is currently some debate as to whether or not these are actually senescent cells. This part of the field is moving fairly rapidly, so answers may well emerge over the next few years, especially given the deployment of senolytic therapies to clear senescent cells into human trials.

Exosomes are the missing link to insulin resistance in diabetes

Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked. Researchers have now identified exosomes - extremely small vesicles or sacs secreted from most cell types - as the missing link. "The actions induced by exosomes as they move between tissues are likely to be an underlying cause of intercellular communication causing metabolic derangements of diabetes. By fluorescently labeling cells, we could see exosomes and the microRNA they carry moving from adipose tissue through the blood and infiltrating muscle and liver tissues."

During chronic inflammation, the primary tissue to become inflamed is adipose. Forty percent of adipose tissue in obesity is comprised of macrophages - specialized immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes. When exosomes get into other tissues, they use the microRNA (miRNA) they carry to induce actions in the recipient cells. The macrophage-secreted miRNAs are on the hunt for messenger RNAs. When the miRNA finds a target in RNA, it binds to it, rendering the messenger RNA inactive. The protein that would have been encoded by the messenger RNA is no longer made. Thus, the miRNAs are a way to inhibit the production of key proteins.

Researchers took macrophages found in adipose tissue of obese mice and harvested their exosomes. Lean, healthy mouse models were treated with these "obese" exosomes and once-normal mice began exhibiting obesity-induced insulin resistance despite not being overweight. When reversing the process, the team found that they could restore insulin sensitivity to obese mice by treating them with exosomes from lean mice. The obese mice remained overweight, but were metabolically healthy. Similarly, during an in vitro study, when human liver and fat cells were treated with "obese" exosomes, these cells became insulin resistant. Conversely, when they were treated with "lean" macrophage exosomes, they became highly sensitive to insulin. "This is a key mechanism of how diabetes works. This is important because it pins the pathophysiology of the disease in inflamed adipose tissue macrophages which are making these exosomes. If we can find out which of the microRNAs in those exosomes cause the phenotype of diabetes, we can find drug targets."

Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity

MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients.

miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that knock out animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of wild type bone marrow into miR-15 knock out mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.