Renegade macrophages—the garbage collectors of the immune system—go rogue in obesity and Type 2 Diabetes

The interrelationship between obesity, type 2 diabetes, complications of diabetes, and immune dysfunction has been suspected for more than a decade1. But it has only been in recent years that many of the threads connecting these conditions have been defined. The diagram below illustrates how energy imbalance in adipose tissue, innate immune activation, and alterations in gut microbiota all contribute to potential chronic inflammation, type 2 diabetes, and diabetic complications.

The starting point for this begins in white adipose tissue where innate immune cells such as macrophages and maturing adipocytes interact as they deal with diet-driven energy imbalances. The latter causes a massive infiltration of macrophages (the big eaters of the immune system) changing their representation in the tissue from 10% to an estimated 40% of cells. These macrophages polarize into a subtype (called M1) that are pro-inflammatory and behave as if they are fighting a never-ending bacterial infection. Specific lipid metabolites use toll-like and NOD receptors on macrophages to activate a protein complex known as the inflammasome, and this further increases cytokine (and other) mediators of inflammation produced by the M1 macrophages.

The macrophage-driven inflammatory attack depletes the maturing adipocyte population causing those cells that survive to swell as they accumulate an inordinate amount of lipids per adipocyte. This progression of the macrophage inflammatory attack in the adipose tissue is bad enough but unlike what happens in Las Vegas, the inflammatory insult does not stay just in the adipose tissue.

Instead, an increasing number of metabolically-intolerant, polarized, renegade macrophages use adipose tissue to stage a war of systemic low-grade chronic inflammation and pathology on an ever-increasing array of metabolically-imbalanced tissues. When they reach a tipping point in numbers and activation state, the adipose tissue macrophages recruit new macrophages from the bone marrow, help to polarize them to M1 cells, and launch a larger inflammatory attack first against the pancreas, and finally in the tissues associated with diabetes co-morbid conditions (such as cardiovascular, neurological, hepatic, and renal disease).

An Immunological Tipping Point

Obesity, by itself, elevates later-life health risks based, in part, on altered immune responses and host defense. It has been associated with  increased morbidity and mortality in the 2009 H1N1 influenza A pandemic. It has also been associated with an increased risk for several non-communicable diseases, and  a shorter lifespan. But often, obesity is only the starting point of the potential health challenges.  As the M1 macrophages activate in obese adipose tissue, their sphere of influence enlarges, and they help increase the activation and mobility status of blood monocytes. Systemic activation of non-adipose tissue macrophages combined with an increase in systemic inflammation appears to signal the transition from obesity to insulin resistance and diabetes. For example, a primary difference between obese women with no diabetes vs. obese women with type 2 diabetes is the level of both circulating proinflammatory cytokines and free fatty acids2. That reflects a tipping point.

As indicated in the diagram, gut microbiota are significant players in obesity and diabetes affecting the risk of these conditions in at least two different ways. First, gut microbes metabolize nutrients producing among other things, short chain fatty acids. Some of these appear to affect tissue inflammation and homeostasis beyond just the gut3. The excess of certain lipids can change the composition of the gut microbiota and signal to macrophages in adipose tissue. Additionally, alterations in the gut microbes can cause the release of lipopolysaccharide (LPS), which has the added effect of activating macrophages and elevating the levels of local and systemic inflammation.

Civilizing Macrophages

Stopping the renegade M1 macrophages as early as possible and/or halting the spreading chronic inflammation offers promise in treating diabetes-related conditions4 with several different observations supporting this approach. For example, in mice when adipose tissue macrophages are engineered to accumulate and metabolize larger amounts of fat, it protects macrophages from inflammatory activation and the mice from obesity. Also in mice, the polyunsaturated fatty acid, resolvin D-1, resolves chronic inflammation, reduces the number of M1 adipose tissue macrophages, and increases the number of wound healing-promoting M2 macrophages. Finally, in rats, the incretin-based drug, dipeptidyl peptidase-4 inhibitor, inhibits macrophage infiltration of the kidney and reduces inflammation, thereby, protecting against the exacerbation of diabetic nephropathy.

Macrophages that infiltrate tissues in response to chemokine signals associated with energy imbalances can promote chronic inflammation, tissue pathology, and disease. The course of macrophage responses to emerging obesity, as reflected in adipose tissues, affects the risk of progression to type 2 diabetes and diabetic co-morbid diseases. Promising therapies are targeting the macrophages and/or the ongoing tissue inflammation they promote.

Citations

  1. Pickup JC, Inflammation and Activated Innate Immunity in the Pathogenesis of Type 2 Diabetes, Diabetes Care March 2004 vol. 27 no. 3 813-82.
  2. van Beek L, Lips MA2, Visser A, Pijl H, Loan-Facsinay A, Toes R, Berends FJ, Willems van Dijk K, Koning F, van Harmelen V. Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance. Metabolism. 2014 Apr;63(4):492-501.
  3. Joyce SA, Gahan CG. The gut microbiota and the metabolic health of the host. Curr Opin Gastroenterol. 2014 Mar;30(2):120-7.
  4. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014 May 23. doi: 10.1038/nrd4275.