"Fasting is not the same for everyone": how 48-hour fasting restructures the immune system differently in thin and obese people

Can a short fast “switch” the immune system to a less inflammatory mode? Researchers from UBC Okanagan, UCSF, and Stanford conducted a controlled experiment: 32 adults (16 obese and 16 non-obese, equally divided between men and women) underwent a 48-hour fast with repeated measurements of metabolism, ketones, and T-cell function. The result: obese people have a weaker trigger for ketosis, poorer T-cell conversion to fat as fuel, and a smaller shift in the balance of anti-inflammatory to pro-inflammatory signals—that is, the immunometabolic “reset” is dulled.

Background of the study

Fasting and intermittent fasting have become a popular strategy in recent years to “reset” metabolism and reduce inflammation. There is biology to this approach: when energy is deficient, the body shifts from glucose to fatty acids and ketones (primarily β-hydroxybutyrate, BHB). Ketones are not only fuel for the brain and muscles, but also signaling molecules: they can suppress inflammatory cascades (e.g., via NLRP3) and change epigenetic marks in immune cells (β-hydroxybutylation of lysines, Kbhb). At the clinical level, this is associated with “calming” low-level inflammation and improving insulin sensitivity.

However, the response to fasting varies from person to person. Obesity is characterized by metabolic inflexibility: a difficult transition from carbohydrates to fat under conditions of calorie deficit. Such “rigid” metabolism affects not only the liver and muscles, but also immune cells. T-lymphocytes, in order to change their function (from pro-inflammatory to regulatory) or to withstand stressful conditions, must switch energy pathways - increase oxidation of fatty acids, adapt mitochondria. If this switch is “tight”, the anti-inflammatory response to fasting may be weaker.

There is also an immunological context. Obesity is often accompanied by a shift towards proinflammatory phenotypes (e.g., Th17/Tc17 and cytokines like IL-17) and an increase in chemokines (MCP-1), which attract monocytes to tissues. Theoretically, ketosis and the signals associated with it should “knock down” this background. But if the BHB level during fasting rises moderately, and its derivatives (including Kbhb) are formed worse, then the “brake” signal on immunity will be quieter - hence the hypothesis that short-term fasting in obese people will provide a more modest immunometabolic benefit.

Finally, a methodological challenge: most data are mixed populations, short observations, and surrogate markers, making it difficult to understand what exactly is changing - systemic metabolism, T-cell mitochondria, cytokine profiles - and how this varies by phenotype (normal weight vs. obese, sex, age). Controlled mechanistic protocols with fixed fasting durations, repeated ketone measurements, immune cell respirometry, and cytokine panels are needed to disentangle the general effects of fasting from phenotype-specific differences and to map out who and how this approach actually benefits.

What exactly was checked?

• Design: 48 hours no calories; visits and blood samples at start, 24 and 48 hours.
• Systemic markers: respiratory quotient (RER), free fatty acids, β-hydroxybutyrate (BHB), BHB-amino acid conjugates, glucose, insulin, leptin.
• Cellular level:
  • Mitochondrial respiration of T cells (including the proportion of “fat” oxphos);
  • T cell subtypes (Th1/Th2/Th17/Th22/Treg);
  • CD4/CD8 expression, IFN-γ and IL-17 secretion;
  • Plasma cytokines (MCP-1, GDF-15, IL-8, IL-6, IL-10, TNF-α, IL-1RA, FGF-21).

Key findings

• Ketosis is blunted in obesity. Increases in BHB, its amino acid conjugates, and lysine β-hydroxybutylation (Kbhb) were weaker in the obese group, despite a similar shift toward body-level fat oxidation.
• Not everyone switches to fat as T cells. In lean subjects, T cells increased their share of fat-oxidative respiration, but not in obese subjects.
• The inflammatory profile is more stable. In the blood of obese people there is more Th17 and higher secretion of IL-17 (especially cytotoxic Tc17), and the shift in anti- to pro-inflammatory cytokines during fasting is less.
• Numbers to remember:
  • MCP-1 decreased in all subjects (≈-27% in lean subjects and ≈-22% in obese subjects) but remained higher in obese subjects.
  • GDF-15 +38% after fasting in lean subjects, no change in obese subjects.
  • IL-8 ↑ by 7% in lean and ↓ by 13% in obese.

What does it mean

Fasting typically switches the body to fats and ketones while simultaneously “calming” the immune system. But in obesity, this duo works less well: ketones rise less, and T cells don’t switch on the “fat” mode to the same extent, which is usually associated with reduced inflammation. So a short fast is not a universal inflammation switch: the response depends on the underlying phenotype.

A bit of mechanics - why are ketones here?

• BHB is not only a “fuel”, but also a signaling molecule: it can suppress inflammatory cascades (for example, NLRP3) and rewire epigenetics through modifications such as Kbhb.
• If the growth of BHB and its derivatives is weaker, then the “signal to disarm” the immune system comes more quietly - a logical explanation for a more persistent inflammatory profile in obesity against the background of fasting.

Where the "pluses" of the post are still visible

• Less MCP-1 - in all groups, that is, monocyte chemotaxis is reduced.
• The systemic shift towards fatty fuels (according to RER) is also happening for everyone.
• For some cytokines (eg, GDF-15), lean subjects show a pronounced response, which may be a marker of adaptation to energy stress.

Practical conclusions

• Fasting is the same tool for all body types: in obesity, the immunometabolic gain may be more modest.
• Combine wisely: Exercise, sleep, calorie deficit, and diet quality are factors that improve metabolic flexibility and likely enhance the immune response to fasting.
• Medical context is important: The 48-hour fast is a research protocol; any long-term restrictions should only be discussed with a doctor, especially if you have diabetes, coronary heart disease, or are taking medications. (Registered Study: NCT05886738.)

How the study was conducted

• Participants: 32 people (16 in each group with normal BMI and obesity; 8/8).
• Protocol: standard breakfast → measurements → 24 hour fast → measurements → 48 hour fast → measurements.
• Methods: indirect calorimetry; BHB-conjugate mass spectrometry; Kbhb immunoblot (PBMC); high-resolution T-cell respirometry; subtype flow cytometry; cytokine multiplex panel.

Restrictions

• The sample size and 48-hour format are mechanistic work, not clinical outcomes.
• The obese group was older on average; the authors took this into account statistically, but residual confounding is possible.
• Research is needed on how to vary protocols (duration, nutrition between episodes, exercise) to equalize the response in obese people.

Authors' comment

The researchers emphasize that the 48-hour fast in their work is a mechanistic stress test, not a treatment protocol. The goal was to understand how quickly and to what extent immune cells switch to the “fat-ketone” mode, and why this response is muted in obese people. The authors’ conclusion is neat: fasting is not a universal inflammation switch; the initial phenotype (obesity/normal) strongly determines the amplitude of the immunometabolic shift.

Specifically, the team notes that obese participants show weaker increases in β-hydroxybutyrate and its derivatives, poorer T-cell increases in fatty acid oxidation, and less pronounced changes in cytokine profiles. This is consistent with the concept of metabolic inflexibility and suggests why similar fasting regimens produce different clinical effects in different people.

What does this mean in practice - according to the authors:

• Personalization rather than “one size fits all”: Fasting protocols may need to be tailored to phenotype (obesity, age, gender) and combined with factors that increase metabolic flexibility (sleep, exercise, diet quality).
• Biomarkers are more important than theory: it makes sense to objectively monitor ketones, the dynamics of inflammatory markers and functional indicators of T-cells, rather than relying on the feeling of “fasting has begun.”
• Without medical romanticism: long-term fasting is not a panacea and not a replacement for therapy; in some people, the expected anti-inflammatory shift may be modest.

The directions that the authors call the next steps are:

• Check what duration/frequency of restrictions and what combinations (for example, exercise before or during fasting) enhance ketosis and “rewire” immune metabolism specifically in obesity.
• To evaluate the role of epigenetic marks (β-hydroxybutylation) as a “memory” of energetic stress and its association with sustained reduction in inflammation.
• Expand the design to larger and more diverse samples, including people with comorbidities, to understand for whom and under what conditions fasting provides practical, meaningful benefits.

Conclusion

Fasting triggers a metabolic “fat-ketone mode” in most people and can dampen inflammation. But in obesity, this response is muted: fewer ketones and their signaling derivatives, a less flexible mitochondrial T-cell response, and a more persistent inflammatory profile. This means that the “fasting to cure inflammation” strategy requires personalization, taking into account the underlying immunometabolism and perhaps support from exercise, sleep, and diet.

Source: Neudorf H. et al. Altered immunometabolic response to fasting in humans living with obesity. iScience 28(7):112872, 2025. DOI: 10.1016/j.isci.2025.112872