Key takeaways
- Chronic low-grade inflammation is persistent systemic cytokine signalling with no resolving event and no symptoms - visible only in markers.
- Visceral adipose tissue is the largest single source, recruiting macrophages and secreting IL-6 and TNF-alpha continuously into circulation.
- Cytokines block insulin signalling by driving serine phosphorylation of insulin receptor substrates, which prevents the tyrosine signal getting through.
- The gonadal axis is suppressed at both ends - hypothalamic GnRH release and Leydig cell steroidogenesis - and thyroid conversion shifts toward reverse T3.
- hs-CRP is uninterpretable as a single value; repeat it, avoid testing near illness, and read the trend.
Chronic inflammation is one of those terms that has been used so loosely it has almost stopped meaning anything. It is worth reclaiming, because the specific version of it — persistent low-grade cytokine signalling, measurable in blood, invisible symptomatically — is one of the few things that genuinely sits upstream of several apparently unrelated problems at once. A man with low testosterone, poor glucose control, a bad lipid panel and low mood does not necessarily have four conditions. He may have one process expressing itself in four places.
What the word actually refers to
Acute inflammation is a controlled emergency response: local, intense, and self-terminating. Blood flow rises, immune cells arrive, the pathogen or damage is dealt with, and resolution signals shut the whole thing down. It is not a problem — it is one of the better pieces of engineering in the body.
Chronic low-grade inflammation is a different state. Cytokines including IL-6 and TNF-alpha circulate at modestly raised levels, continuously, without a resolving event. It is systemic rather than local, mild rather than intense, and it produces no symptoms you can point to. What it does instead is alter how other cells behave — because these cytokines are signalling molecules, and every tissue exposed to them adjusts its behaviour accordingly. The ageing-related version of this state is described as inflammaging, and the case for it as a shared driver of age-related disease is now reasonably well developed (Franceschi et al., Nat Rev Endocrinol 2018).
Because it is silent, it is only visible in markers. hs-CRP is the practical one — an acute-phase protein made by the liver largely in response to IL-6, so it functions as a downstream readout of how much inflammatory signalling is going on. It tracks cardiovascular risk in large-scale epidemiology (Kaptoge et al., Lancet 2010).
Where the signal comes from
The largest single source in most people is visceral adipose tissue, and the mechanism is worth knowing because it explains why this marker is so responsive to body composition.
Adipose tissue is not inert storage. As fat cells expand beyond their comfortable capacity they become hypoxic and stressed, and they recruit macrophages. Those macrophages, together with the adipocytes themselves, secrete IL-6 and TNF-alpha directly into the portal and systemic circulation. Visceral fat does this more than subcutaneous fat, and it drains straight to the liver. So the depot is functioning as an endocrine organ that broadcasts a continuous inflammatory signal proportional to how overloaded it is. Visceral fat and its relationship with testosterone both run through this mechanism.
Other significant contributors: obstructive sleep apnoea and fragmented sleep, through intermittent hypoxia and sympathetic activation; chronic psychological stress; gut barrier dysfunction; periodontal disease and other low-grade infections; smoking; excess alcohol; inactivity; and a diet heavy in ultra-processed food and light in omega-3.
How it breaks insulin signalling
This is the most direct mechanism and the one with the clearest evidence. Insulin works by binding its receptor, which then phosphorylates insulin receptor substrate proteins on tyrosine residues, propagating the signal that moves glucose transporters to the cell surface.
Inflammatory cytokines activate intracellular kinases that phosphorylate those same substrate proteins on serine residues instead. Serine phosphorylation blocks the tyrosine signal. The insulin is present, the receptor is present, and the message does not get through. The pancreas responds by producing more insulin, which is why fasting insulin rises long before glucose does.
The loop closes on itself: insulin resistance promotes fat storage, particularly visceral, which produces more cytokines, which worsens insulin resistance. That self-reinforcing quality is why reversing insulin resistance tends to require breaking the loop at more than one point.
How it suppresses the hormonal axes
Inflammation acts on the gonadal axis at both ends. Centrally, cytokines suppress hypothalamic GnRH release, lowering LH drive. Peripherally, IL-6 and TNF-alpha directly impair Leydig cell steroidogenesis, so even the LH that arrives produces less testosterone (Tremellen, Basic Clin Androl 2016). Adipose aromatase adds a third effect by converting more testosterone to oestradiol, and the resulting feedback suppresses the axis further.
The thyroid axis is affected differently. Inflammation and cortisol shift deiodinase activity so that more T4 is converted to reverse T3 rather than active T3 — a downregulation of metabolic rate that shows up as normal TSH with low free T3, and is covered in reverse T3 under chronic stress. Cortisol itself rises as part of the response and contributes its own dysregulation.
The practical consequence: a man with obesity-driven inflammation and low testosterone has two candidate explanations, and only one of them is corrected by testosterone. Treating the hormone without addressing the source leaves the driver running.
Reading the markers properly
hs-CRP is the workhorse, and it has one behaviour that trips people up constantly: it responds massively to acute events. A cold, a dental infection, a hard training session in the preceding days or any minor illness can multiply a result. A single high value therefore means very little on its own.
The rules that make it usable: repeat it before acting, take the lower of two readings taken a few weeks apart, avoid testing within a couple of weeks of illness, and track the trend rather than any one point. Supporting markers add context — fibrinogen, the neutrophil-to-lymphocyte ratio from a standard blood count, ferritin as an acute-phase reactant, and the omega-3 index as a modifiable input. hs-CRP in detail and the wider inflammatory panel cover the interpretation.
What lowers it, in order of leverage
The interventions are not equal, and treating them as an undifferentiated list is why people start with the smallest one.
- Reduce visceral fat. The largest lever by a distance, because it removes the source rather than opposing the signal. Anything that achieves this — dietary change, training, or a medication where clinically indicated — tends to move inflammatory markers with it.
- Fix sleep, and treat sleep apnoea if present. Untreated apnoea maintains a nightly inflammatory stimulus that no dietary change will offset.
- Train regularly. Exercise produces a transient inflammatory spike and a lower chronic baseline; meta-analysed trial data supports reduction in CRP with structured training (exercise training and C-reactive protein, meta-analysis of randomised trials).
- Change the dietary pattern rather than adding a supplement. A Mediterranean-pattern diet, adequate fibre, and enough omega-3 to bring the index above roughly 8% — see the omega-3 index.
- Limit alcohol, stop smoking, treat periodontal disease, each of which removes a persistent stimulus.
- Address chronic psychological load, which is the least measurable item here and not the least important.
The honest limit of the theory
It would be convenient if inflammation were simply a switch to turn down pharmacologically, and the field has tested that. Targeted interleukin-1-beta inhibition reduced cardiovascular events without changing lipids, which is genuine proof that the inflammatory pathway is causal rather than merely correlated (Ridker et al., Eur Heart J 2018). It also increased fatal infection, which is the predictable cost of suppressing part of the immune system in an unselected population.
The causal claim survives; the therapeutic shortcut does not. Which leaves the unglamorous route: remove the sources of the signal rather than block the signal.
The clinical insight: several problems that get treated as separate — low testosterone, insulin resistance, a poor lipid panel, low free T3, low mood — can share one upstream driver. That does not mean every case is inflammatory. It means that when a panel shows a cluster rather than a single abnormality, the cluster itself is the finding, and treating each item individually will underperform.
Bottom line
Chronic low-grade inflammation is a real, measurable state, driven most often by visceral fat, poor sleep, inactivity and diet. It interferes with insulin signalling at the receptor substrate, suppresses the gonadal axis at both the hypothalamus and the testis, and shifts thyroid conversion toward the inactive form — which is why it produces a scattered panel that looks like several separate conditions. Measure it with hs-CRP, reading the trend rather than a single value, and lower it by removing sources in order of leverage, starting with visceral fat and sleep.
Educational content, not medical advice. Laboratory interpretation and any treatment decision are made by a licensed physician after individual evaluation. Individual results vary.
