Do you like to know how things work on the biochemical level? Are you tired of popular articles glossing over all the fascinating science in favor of shirtless pictures of Ryan Gosling cuddling kittens? If so, this is for you.
Here are all the fun details of why you can blame bad fat for metabolic dysfunctions and whole body inflammation. We include all references for even more reading fun!
Consuming too much sugar, chips or just food in general causes nutrient overload. The excess calorie energy and/or the whole body inflammation that comes with it causes fat cells to grow abnormally large (hypertrophic) and spew inflammatory chemicals.
These extra thick adipose (fat) cells are physically and metabolically dysfunctional. Large adipose cells display metabolic, epigenetic and physical abnormalities when compared to smaller healthy adipose cells (Longo et al. 2019). Changes include larger size, altered adipokine (chemical) secretion, impaired glucose translocation (harder to move glucose around), abnormal differentiation into mature adipocytes, a disorganized cortical actin (this determines cell shape and surface tension), a unilocular-like lipid droplet (the fat is all in one giant lipid drop), and abnormal lipid metabolism (discussion in Choe et al. 2016 and Longo et al. 2019). These changes are correlated with low-grade inflammation, insulin resistance (IR), and increased type 2 diabetes (T2D) risk (discussion in Ahmed et al. 2021).
The cellular cortex is a meshwork of thin actin filaments bound to the cell's plasma membrane. These filaments control cell shape, cell morphogenesis, and surface tension (for more see Chugh and Paluch 2018). Cortical actin organization is associated with adipogenesis (creation of new fat cells), triglyceride accumulation, lipid droplet formation, and glucose transporter (GLUT4) trafficking (moving glucose transporters around) (Schiller et al. 2013).
GLUT4 is a sugar transporter. It is a key regulator of whole-body glucose homeostasis (glucose balance). GLUT4 allows insulin-stimulated glucose uptake into most cells of the body including muscle and fat tissue.
Dysregulation of cortical actin in hypertrophic adipose cells causes impairment of insulin-dependent GLUT4 plasma membrane translocation (Kim et al. 2015). This decreases glucose diffusion into the cell. Fat cells with enlarged uniloculus-like lipid droplets have decreased insulin-dependent uptake ability and become IR even without the accompanying inflammation (Kim et al. 2015).
In addition, larger fat cells have reduced GLUT4 delivery to the plasma membrane and reduced GLUT4 dispersal when compared to smaller fat cells (Koester et al. 2022).
Recent research suggests that people who are obese may have an abnormal fat cell distribution with a combination of too many large and too many tiny fat cells. Both the extremely small adipocytes and the extra chunky ones were unable to expand for energy storage which lead to insulin resistance and abnormal metabolism. Adipocytes become stiff with abnormal cell membrane signaling (discussion Stenkula et al. 2018).
Compared to lean adipocytes, hypertrophic adipose tissue releases more free fatty acids (FFAs) and inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), serum amyloid A (SAA), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) (see discussion Longo et al. 2019 and Kawai et al. 2020). Inflammatory cytokines attract immune cells which flood into adipose tissue (Kawai et al. 2020).
Adipose tissue macrophages (ATM) can make up 40-60% of the immune cells in adipose tissue (immune cells especially like to hang out in visceral fat). In the obese state ATM recruitment triggers an inflammatory feedback loop that further increases adipocyte impairment, metainflammation and IR (Weisberg et al. 2003, Xu et al. 2003).
Diet induced obesity shifts ATMs from M2 or alternately activated macrophages to M1 or classically activated macrophages. So why does this matter? Compared to M2 ATMs, M1 ATMs have a higher output of the inflammatory cytokines TNF-α, IL-6 and IL-12 and generate more reactive oxygen species such as NO through activation of iNOS. This increases insulin resistance (IR) (Lumeng et al. 2007).
Dysfunctional fat cells cause hypoxia, which is oxygen restriction to an area. The combination of pathological adipose tissue remodeling, inflammation and impaired vascularization (less blood vessels grow into the area) in metabolic disorder results in oxygen deficiency and reduced insulin sensitivity (Spencer et al. 2011, Oliva-Olivera et al. 2017, Corvera et al. 2022). Oxygen restriction further impairs vascularization, increases immune cell recruitment, dysregulates adipokine production and increases adipocyte death (Choe et al. 2016). Lack of vascularization can also impair glucose equilibrium. In healthy adipose tissue, angiogenic capacity is associated with glucose homeostasis (Du et al. 2021).
Hypoxia triggers endoplasmic reticulum (ER) stress leading to the misfolded protein response. Proteins are created as a string of amino acids. They need to be folded in the ER to make a 3-D shape to function correctly. Lack of oxygen and/or inflammation can stress out the ER and cause proteins to be misfolded.
Misfolded protein response activates stress and inflammation pathways while interfering with insulin regulation (Snel et al. 2012). In vitro studies have shown that ER stress contributes to IR through JNK-mediated serine phosphorylation of IRS1 (Özcan et al. 2004). In this process, JNK (c-Jun N-terminal kinase) adds phosphate groups to serine (an amino acid) found on proteins. This can influence the protein's functions.
In spite of the name, LOX is not a tasty brined addition to your morning bagel. It is a copper enzyme (cuproenzyme) that helps assemble the extracellular matrix (proteins that surround and support cells) by oxidizing lysine residues in elastin and collagen. LOX helps form connective tissue and keeps your teeth, bones, skin and blood vessels from falling apart.
Basically, the toxic mix of hypoxia and inflammation upregulates LOX; this cuproenzyme prompts posttranslational modification of fiber-forming extracellular matrix components - say that fast five times (Pastel et al. 2018). Unfortunately, excessive LOX results in stiff and scarred fat cells which are less able to expand and adapt to nutrient storage needs (Pastel et al. 2018).
This increase in adipose tissue fibrosis may be an adaptive response to lessen the metabolic effects of larger fat cells by limiting their cell size (Muir et al. 2016). However, when fat cells are unable to expand, fat deposits build up in less desirable areas such as around the internal organs. This excess fat in the heart and lungs can become stiff and fibrous (Pastel et al. 2018).
Stressed and battle scarred fat tissue is less able to take up and release dietary energy. This means excess LOX contributes to the pathology of MetS; in particular by contributing to the decrease in metabolic flexibility (Miana et al. 2015, Pastel et al. 2018). People with scarred fat tissue may also have a hard time losing weight.
LOX up-regulation observed in MetS may be a significant cause of the increased risk of cancer, CVD, hypertension and nonalcoholic fatty liver disease (NAFLD) (Pastel et al. 2018, Rodríguez and Martínez-González 2019, Li et al. 2024). LOX is highly expressed (produced) in invasive tumors. It accelerates tumorigenesis and metastasis by actively remodeling the microenvironment around the tumor while facilitating tumor adhesion at the metastatic site. High LOX expression is linked with tumor metastasis and poor patient outcome (Li et al. 2024).
Increased LOX activity can contribute to cardiac disease. LOX augments myocardial oxidative stress in part through generation of H2O2 and NADPH oxidase 4 (NOX4) (Rodríguez and Martínez-González 2019).
By the way, while up-regulation of LOX increases obesity; down-regulation of LOX can have the opposite effect. Lower LOX levels stimulate some white fat cells to turn into beige fat cells. Unlike white fat cells, which store extra calories, beige fat cells release extra energy as heat (Xing et al. 2020). This could help combat obesity.
Accelerated adipocyte death causes necrosis (cell death) and the development of localized inflammation sites. Attracted by dying cells and inflammatory cytokines, large numbers of macrophages infiltrate adipose tissue, phagocytosing the dying cells while encasing them in crown-like structures to protect surrounding tissue (Cinti et al. 2005, Chavakis et al. 2023).
During this process, macrophages often fuse together in multinucleate giant cells. Since even one dead adipocyte can attract many ATMs, the mass of fused ATMs, dead cells, free lipid droplets from ruptured necrotic fat cells, and crown-like structures become local focal points of chronic inflammation which can last for months or become encapsulated (Cinti et al. 2005). Multinuclear giant cells produce proinflammatory cytokines, interleukin-1, and TNF-α, which increase inflammation. This cellular necrosis and adipose tissue remodeling during obesity contributes to IR and inflammation in the pathology of obesity (Cinti et al. 2005, Hildebrandt et al. 2023).
Unlike dysfunctional adipose cells, skeletal muscle myocytes do not appear to secrete additional inflammatory cytokines themselves. Most of the inflammation is caused by a combination of dysfunctional adipose cells residing in the muscle and the infiltration of immune cells (macrophages and T-cells) who transform into proinflammatory phenotypes. Fat in the muscle is called intermuscular adipose tissue (IMAT). It may sound like a 90's 3-D movie theater, but it can have devastating effects on your health.
These fat cells have a distinct origin story. Whole body inflammation transforms innocent stem cells, called fibro-adipogenic progenitors (FAPs), within the muscle into evil fat cells (Flores-Opazo et al. 2024). FAPs are stroma stem cells. Stroma cells are a diverse group of connective tissue cells that help regenerate, stabilize and maintain tissue. FAPs can turn into adipocytes, fibroblasts or osteocytes (under certain conditions). When FAPs change into adipose cells it contribute to IMAT pathology.
So what you may say? Well, IMAT is associated with many common diseases including metabolic disorders like obesity, T2D, insulin resistance (IR), fatty liver, and CVD; immunometabolic and hormonal disturbances; chronic muscle disease and wasting, inflammatory muscle disorders, sarcopenia (see discussion in Flores-Opazo et al. 2024). IMAT infiltration is associated with unhealthy aging and muscle deconditioning due to physical inactivity (see Zhang et al. 2023, figure 1 in Flores-Opazo et al. 2024).
Muscle inflammation, as measured by serum C-reactive protein (CRP) and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interfere with cell protein synthesis to contribute to age related muscle loss, sarcopenia, as well as cancer cachexia (Wåhlin-Larsson et al. 2018, Setiawan et al. 2023). Rising levels of TNF-α cause muscle wasting by induction of the ubiquitin-proteasome system (UPS). The UPS is one of two main pathways that oversees protein quality control by degrading and clearing old or damaged proteins and organelles. Metabolic disease has also been shown to cause dysregulation of the autophagy-lysosome pathway, which is the second pathway responsible for bulk degradation of intracellular organelles and protein aggregates (Ren and Xu 2015).
The combination of proteotoxicity, which is the result of poor protein quality control, and abnormal autophagy may be responsible for some of the pathophysiology of metabolic dysregulation, NAFLD, and cardiometabolic disease (Ren and Xu 2015, Zhang et al. 2018). As TNF-α concentrations increase, there is an increase in gluconeogenesis, adipose tissue loss and proteolysis, coupled with a decrease in protein, lipid and glycogen synthesis (Patel and Patel 2017). There is also evidence that UPS increases inflammation and oxidative stress (discussion Qiu et al. 2022). A reduced resting energy expenditure (REE) is associated with an increase in genes involved in up-regulation of UPS (Wu et al. 2011). This can enhance the weight gain typically seen with MetS.
The inflammation pathways involved in this process contribute to IR by impairing insulin signaling in myocytes (Wu and Ballantyne 2017, Fazakerley et al. 2019). As IR increases it accelerates muscle protein degradation while suppressing protein synthesis (discussion in Liu and Zhu 2023). Since skeletal muscle regulates insulin stimulated glucose disposal throughout the body; disruption of this system can affect whole-body glucose homeostasis as well as insulin sensitivity (Wu and Ballantyne 2017).
Oxidative stress can be initiated and maintained by dysfunctional adipose tissue (Manna and Jain 2015). Impaired adipose tissue, chronic inflammation, inflamed mitochondria and increased LOX production generates reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) which promote oxidative stress (discussion in Colak and Pap 2021). Adipocytes exposed to excess energy from glucose or fatty acids increase oxidative stress by activating NADPH oxidase which promotes ROS production. Increased ROS production causes a feedback loop by promoting dysregulated adipocytokine expression, increasing IR and upregulating mRNA expression of NADPH oxidase (Furukawa et al. 2004). There is a significant correlation between oxidative stress biomarkers and individual metabolic risk factors like body mass index (BMI), waist circumference, and adipose accumulation (discussion Masenga et al. 2023).
Oxidative stress is closely aligned with energy metabolism, adipocytokine differentiation and the development of MetS (discussion Maslov et al. 2018). Oxidative stress itself may initiate MetS by amplifying insulin signaling pathways. High concentrations of ROS, specifically H2O2, stimulate the same pathways as insulin and multiply the downstream effects of insulin. H2O2 is a second messenger molecule in insulin signaling (discussion Lennicke and Cochemé 2021). Excess H2O2 prompts fat and muscle cells to take up glucose. At the same time, it promotes adipocyte expansion by stimulating GLUT4 translocation and lipid synthesis (Bonomini et al. 2015). This can kick off the metabolic disturbances leading to MetS. In addition, oxidative stress reduces insulin sensitivity, promotes visceral obesity, aids hypertension, alters mitochondrial dynamics, and impairs glucose and lipid metabolism which also contributes to the development and pathology of MetS (Furukawa et al. 2004, Bonomini et al. 2015, Li et al. 2022).
Mitochondria dysfunction and/or ROS activate large caspase-1-activating multiprotein complexes known as inflammasomes. Inflammasomes are part of the immune system. When inflammasomes detect pathogenic organisms or cellular stress, they activate caspase-1. Caspase-1 triggers proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 to mature which leads to pyroptosis, a form of programmed cell death (discussion in Chen et al. 2023).
Inflammasome activation accelerates multiple pathways which damage mitochondria by inducing disassembly, increasing ROS production, and inhibiting mitophagy, an important process to maintain a healthy mitochondria pool by removing damaged mitochondria through autophagy pathways. This disrupts mitochondria networks resulting in increased dysfunctional mitochondria and inflammation. Inflammasome activation may be a risk factor for IR, metabolic diseases and further mitochondria degradation (discussion in Chen et al. 2023).
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*Mara B (32 year old woman): "... I need to be healthy to have a life that I enjoy. I want to be able to enjoy physical activities, to be in good overall health, to reduce my risk for serious diseases like heart disease and even cancers. I have three young kids, two girls and a boy, and I want to be around for them as long as possible.
I stopped hyperfocusing on weight loss and started focusing on making my body stronger. I lifted heavier weights, walked farther, walked faster and just did more. I ate better to support muscle growth and reduce inflammation. I started thinking of eating better as something I did FOR ME. It is a gift to be healthier.
It feels different when you lose body fat and build muscle. Now I feel strong when I am active. I can lift my toddler easily and run after two older kids.
Being fit allows me to feel my best and look better too. I lost a few inches around my belly. When I am at a lower fitness I feel sloppy. I do not enjoy activities or life as much and I feel worse every day."
*Names and some minor identifying details in all stories in this website are changed to protect people's privacy.
This information is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.
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