Macrophages are immune system cells. They are essential in the early response to infections, and they also have a key role in the proper functioning of our tissues and the regulation of obesity.
Now, researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have shown how this regulation unfolds in a paper published in Nature Metabolism, which could be useful to design new treatments for the obese and overweight, and for some associated pathologies, including fatty liver disease and type 2 diabetes.
The study was led by CNIC researchers directed by Dr. José Antonio Enríquez and Dr. David Sancho.
It was completed in collaboration with the David Geffen School of Medicine and the Department of Medicine/Division of Cardiology of the University of California, Los Angeles (UCLA), in the US; the University of Eastern Finland and the Kuopio University Hospital (Finland); and the University of Salamanca and the Complutense University of Madrid.
It explains how the activation of the mitochondrial metabolism of macrophages in response to oxidative stress due to excess nutrients contributes to fatty tissue inflammation and obesity.
“In recent decades, several studies have verified that fatty tissue macrophages facilitate an anti-inflammatory and reparative environment in normal conditions.
This contributes to deactivating any processes altering the normal functioning of these tissues.
These are known as anti-inflammatory or ‘type M2’ macrophages,” Dr. Enríquez explains.
In certain cases, he adds: “The M2 macrophages interpret that there are stress signals, normally arising in response to infection, and they foster inflammation as a defense mechanism.”
These inflammation processes sourced to macrophages, says Dr. Enríquez, are responsible for the emergence of fatty tissue alterations, and “are the origin of obesity and the metabolic syndrome associated to cardiovascular disorders, fatty liver disease and type 2 diabetes.”
This means that, as a response to the excess nutrients created by a high-fat diet, “macrophages change their function and support inflammatory processes, forming ‘type M1’ proinflammatory macrophages.”
Mitochondrial metabolism changes
The research now published has analyzed how macrophage metabolic changes regulate this inflammatory process, which underlies obesity and the metabolic syndrome.
The new findings, says Dr. Rebeca Acín-Pérez (currently at UCLA), “reveal how the detection by macrophages of oxidative danger signals – known as reactive oxygen species – leads to mitochondrial metabolism changes of these immune cells, needed to distinguish them from an M1 proinflammatory type.”
This oxidative stress, she clarifies, is found in morbidly obese patients, and it seems to be related to a high-fat diet, commonplace in the inadequate Western diet.
One of the conditions of this study, Dr. Sancho says, is that it proves that when this oxidative stress is reduced, “it ameliorates some of the harmful parameters associated with obesity.”
In previous studies, CNIC scientists had found that the Fgr protein is decisive in regulating one of the complexes of the transport chain of mitochondrial electrons – the II complex – in response to this oxidative stress, and to benefit the generation of signals (cytokines and metabolites) fostering immune responses.
Salvador Iborra says that this study “proves that this same molecular mechanism regulates the conversion process of an anti-inflammatory macrophage (M2) governing the function of the tissue to a proinflammatory macrophage (M1), where lipid droplets accumulate. A balance between both types of M2/M1 macrophages is crucial for the proper functioning of the body.”
Although inflammation is a normal body response and it is beneficial to face acute and transitory threats, it is very damaging when it becomes persistent or chronic, even in low-grade inflammation scenarios.
The researchers explain that this happens in obesity and the metabolic syndrome, and it leads to increased cardiovascular mortality and diabetes.
The information contained in this new paper proves that, in the absence of the Fgr protein, the liver increases its ability to eliminate fat by generating ketone bodies (chemical compounds produced by ketogenesis, a process using body fats as an energy source), which are eliminated in the urine, and that this further enhances the alterations of obesity to the glucose metabolism (type 2 diabetes).
The results, found in mice, have been corroborated by human cohorts, where the authors found a stark correlation of Fgr and the negative consequences of obesity.
The researchers conclude that their data suggest the potential of using specific Fgr protein inhibitors to treat obese and/or metabolic syndrome patients.
The goal would be reducing the associated inflammation, thereby improving the parameters associated with these illnesses, like fatty liver and type 2 diabetes, and contributing to raise patients’ life expectancy and quality.
Obesity is a major health problem, and it is involved in the development of heart diseases, cerebrovascular accidents, cancer, fatty liver disease, metabolic syndromes, high blood pressure and some autoimmune diseases.
A combination of an excess intake of nutrients, a lack of physical activity and genetic risk factors leads to an imbalance of energy demanded vs. energy consumed, and this is where obesity starts.
In Spain alone, it is expected that in only a decade (by 2030), there will be 27 million obese and overweight adults (80% men and 55% women).
Electron ﬂux in the mitochondrial electron transport chain is determined by the superassembly of mito- chondrial respiratory complexes. Different superas- semblies are dedicated to receive electrons derived from NADH or FADH2, allowing cells to adapt to the particular NADH/FADH2 ratio generated from avail- able fuel sources.
When several fuels are available, cells adapt to the fuel best suited to their type or func- tional status (e.g., quiescent versus proliferative). We show that an appropriate proportion of superas- semblies can be achieved by increasing CII activity through phosphorylation of the complex II catalytic subunit FpSDH.
This phosphorylation is mediated by the tyrosine-kinase Fgr, which is activated by hydrogen peroxide.
Ablation of Fgr or mutation of the FpSDH target tyrosine abolishes the capacity of mitochondria to adjust metabolism upon nutrient re- striction, hypoxia/reoxygenation, and T cell activa- tion, demonstrating the physiological relevance of this adaptive response.
To utilize fuels efﬁciently, cells must exquisitely integrate the ac- tivities of membrane receptors and transporters, the intracellular compartmentalization of molecules, the enzymatic balance of each metabolic step, and the elimination of byproducts (Stanley et al., 2013).
Appropriate orchestration of all these changes is critical for the cell’s ability to adapt to changing functional requirements, such as quiescence, proliferation, and differen- tiation, and to environmental changes, including survival in response to diverse insults.
Factors known to inﬂuence this adaptation include the cellular response to oxygen availability (hypoxia-inducible factors HIF1a and HIF1b); regulators of energy availability such as mammalian target of rapamycin (mTOR), AMP-activated protein kinase, sirtuin, and forkhead box (FOX)O; and mediators of the response to reactive oxygen
species (ROS), such as peroxisome proliferator-activated recep- tor gamma coactivator-1 alpha (PGC-1a). The involvement of these factors illustrates the interconnection between the use of alternate carbon substrates (carbohydrates, amino acids, fatty acids and ketone bodies) and the cellular response to stress, particularly oxidative stress.
At the core of this process are mitochondria. In response to changes in fuel source, mitochondria must modify their location, structure, and metabolite ﬂuxes in order to balance their contribution to anabolism (lipogenesis and antioxidant defenses from citrate, gluconeogenesis, serine and glycine biosynthesis from pyruvate, nucleotide biosynthesis) and catabolism (TCA cycle, b-oxidation, oxidative phosphorylation).
Mitochondria are central to ATP synthesis, redox balance, and ROS production, pa- rameters directly dependent on fuel use.
All catabolic processes converge on the mitochondrial electron transport chain (mETC) by supplying electrons in the form of NADH+H+ or FADH2. The relative proportion of electrons supplied via NADH and FADH2 varies with the fuel used; for example, oxidative metabolism of glucose generates a NADH/FADH2 electron ratio of 5, whereas for a typical fatty acid (FA) such as palmitate the ratio is z2 (Speijer, 2011).
Our recent work on the dynamic architecture of the mETC re- veals that supercomplex formation deﬁnes speciﬁc pools of CIII, CIV, CoQ, and cyt c for the receipt of electrons derived from NADH or FAD (Lapuente-Brun et al., 2013).
Since CIII preferen- tially interacts with CI, the amount of CI determines the relative availability of CIII for FADH2– or NADH-derived electrons. The regulation of CI stability is thus central to cellular adaptation to fuel availability.
A substrate shift from glucose to FA requires greater ﬂux from FAD, and this is achieved by a reorganization of the mETC superstructure in which CI is degraded, releasing CIII to receive FAD-derived electrons (Lapuente-Brun et al., 2013; Stanley et al., 2013).
Failure of this adaptation results in the harmful generation of reactive oxygen species (ROS) (Speijer, 2011). The proportion of supercomplexes dedicated to receiving NADH electrons is further dependent on the structure and dynamics of mitochondrial cristae (Cogliati et al., 2013; Lapuente-Brun et al., 2013), so that reducing the number of cristae favors ﬂux from FAD.
In agreement with this, ablation of the mitochondrial protease OMA1, which prevents optic atrophy 1 (OPA1)-speciﬁc proteolysis and cristae remodeling,impairs FA degradation in mice, resulting in obesity and impaired temperature control (Quiro´ s et al., 2012).
Cells are normally exposed to a mixed supply of fuels, but despite this, cells are often predisposed to preferentially use one source over another, according to their physiological role or status (Stanley et al., 2013).
T cells, for example, switch from oxidative to glycolytic metabolism upon activation, coin- ciding with entry into a proliferative state, and later increase FA oxidation when they differentiate into regulatory T cells. These changes require remodeling of the mETC NADH/FADH2 ﬂux ca- pacity, but how cells regulate this choice of carbon source is not understood.
Here, we show that fuel choice is regulated via tyrosine phos- phorylation of complex II (CII) subunit FpSDH, mediated by ROS- activation of the tyrosine kinase Fgr.
This activation is required to adjust the level of complex I (CI) to optimize NADH/FADH2 electron use. Our data show this mechanism operating in three physiological situations: upon T lymphocyte activation, in the adaptation of liver and cultured cells to starvation, and in the adaptation of cells to hypoxia/reoxygenation.
More information: Rebeca Acín-Pérez et al, Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity, Nature Metabolism (2020). DOI: 10.1038/s42255-020-00273-8