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OBESITY

Ketogenic diet and adipose tissue

inflammation—a simple story? Fat chance!
A new study in mice reveals time-dependent effects of a ketogenic diet on resident immune cells in visceral
adipose tissue, which have consequences for whole-body metabolic homeostasis.

Brianna J. Stubbs and John C. Newman

T
he insidious expansion of the
global obesity epidemic and related
chronic health complications such
as cardiovascular disease, diabetes and
cancer is impossible to ignore. Nutritional Ketogenic diet

interventions to combat this epidemic

are widely studied clinically, but much
remains to be learned about their molecular
mechanisms of action. One molecular
hallmark of caloric excess and obesity
is chronic inflammation, particularly in
visceral adipose tissue (VAT). Over time,
obese VAT becomes increasingly populated
by pro-inflammatory immune cells, and the
proportion of anti-inflammatory regulatory
cells declines1. In the current issue of
Nature Metabolism, Goldberg et al. show
that short-term feeding of a ketogenic diet
(KD) changes the mix of innate immune
cells in visceral adipose tissue, thus resulting
in decreased inflammation and improved
biomarkers of metabolic health2. The results
parallel the authors’ recent finding that the
KD similarly reprograms the mix of innate
immune cells in the lungs, thus protecting
mice from influenza3. However, the authors
went on to show that these beneficial effects
in visceral adipose tissue were reversed when
long-term KD feeding resulted in obesity.
Their results shed light on the interaction
between nutrition and immunity, as well as
the temporal progression of diet-induced
inflammation in adipose tissue.
KDs are increasingly being studied as a
nutritional tool for weight loss and treatment
of type 2 diabetes. The KD involves severely
limiting carbohydrate intake, maintaining
moderate protein intake and consuming
most daily caloric needs from healthful fats.
Over time, metabolic adaptations to the KD
occur, such as a decrease in carbohydrate
metabolism, an increase in both lipid release
and oxidation, and greater conversion
of free fatty acids into ketone bodies. In
humans, the KD has been shown to be a
safe and efficacious option for weight loss
and improvement of metabolic control, and
recent multi-year studies have demonstrated
Nature Metabolism | VOL 2 | January 2020 | 3–4 | www.nature.com/natmetab
1 week 2–3 months
lean obese
Visceral
adipose
tissue
γδ T cells Macrophages
Metabolic homeostasis Inflammation
Metabolic dysregulation
Fig. 1 | A ketogenic diet alters resident immune cells in visceral adipose tissue in a time-dependent
manner. Mice fed a high-fat, zero-carbohydrate KD for 1 week show increased VAT-resident γδ T cells
with a unique protective gene expression signature, and a decrease in pro-inflammatory macrophages
and IL-1β levels. However, 2–3 months of the KD, which in these mice causes obesity, reverses these
changes and decreases γδ T cells while increasing macrophages. Knocking out γδ T cells exacerbates
the metabolic and immunological dysfunction of long-term obesogenic KD consumption.
improved long-term blood-glucose control despite not resulting in significant weight
and decreased use of diabetes medication change (Fig. 1). The VAT of KD-fed mice
in obesity and type 2 diabetes4,5. The contained fewer macrophages and more B
major ketone body produced on the KD, and T cells, including double the population
β-hydroxybutyrate (BHB), not only provides of γδ T cells. γδ T cells are an unusual
a non-glucose energy source to cells but innate-like T cell population that is activated
also has direct protein-binding signalling by cytokines and pattern-recognition
activities6. Indeed, the authors of the current receptors rather than T cell–receptor signals.
study discovered that BHB directly inhibits They are best known for antimicrobial
the assembly and activation of the NLRP3 functions in barrier tissues such as the
inflammasome7, which is a key regulator skin and lung. Indeed, the authors have
of the innate immune system and has been recently reported that 1 week of the KD
implicated in obesity-related inflammation similarly increased the γδ T cell population
and disease8. This finding led the authors in the lung, an effect associated with airway
to hypothesize that the KD might have epithelial remodelling and protection
a beneficial effect on innate-immune- against influenza morbidity and mortality3.
metabolic regulation of inflammation In VAT, the decline in macrophages and
within VAT. expansion of γδ T cells was associated with
One week of KD feeding to normal mice a decreased gene expression signature of
altered the immune-cell composition of VAT the NLRP3 inflammasome and lower levels
3
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of the inflammatory cytokine IL-1β, which
is released by activated NLRP3. Single-cell
RNA sequencing revealed a unique gene
expression signature involving protective
tissue remodelling and fat metabolism
induced by the KD in γδ T cells. This
finding also paralleled the effects of the KD
on γδ T cells in the lung, which featured a
unique gene expression signature involving
fat metabolism and redox balance. Whereas
γδ T cells migrate into other tissues
including the lung, an intravascular labelling
technique, along with parabiosis, in which
the circulatory systems of two mice are
conjoined, confirmed that γδ T cells in VAT
are uniquely tissue resident. One week of
KD feeding appeared to alter the abundance
and phenotype of VAT γδ T cells in situ.
Although humans generally lose weight
on KDs, mice often overeat and become
obese on these very high-fat diets. If
overeating is prevented by fixed-calorie
feeding or diet cycling, the KD extends the
healthy lifespan in mice9,10, but mice that
overeat the KD to the point of obesity have
shorter lifespans9. Thus, the authors also
tested whether these innate immune changes
in VAT persisted as mice became obese on
the KD over several months; the changes
did not persist. Long-term KD feeding
resulted in more macrophages and fewer γδ
T cells in VAT, the opposite of the results
after short-term feeding. The immune-cell
changes were associated with higher levels
of inflammatory IL-1β and increased insulin
4 Nature Metabolism | VOL 2 | January 2020 | 3–4 | www.nature.com/natmetab
resistance. Is the short-lived boost in VAT
γδ T cells on the KD, then, briefly protective
or a trigger for harm? The population of γδ
T cells can be eliminated entirely by using a
mouse genetic knockout of Tcrd, the T cell
receptor for γδ T cells. These mice lack γδ
T cells entirely and, when fed the KD, show
exaggerated metabolic and inflammatory
dysfunction, including an even higher
proportion of macrophages in VAT.
The two studies from Goldberg et al.
provide provocative examples in two
distinct tissues (VAT and lung) of how
nutrition can affect major health outcomes
(metabolic disease and influenza) by
modulating resident innate immune cell
populations. Yet key questions remain.
The mechanism by which the KD affects
macrophage and B or T cell populations
is not clear, and unexpectedly may not
involve circulating BHB. Like the KD,
a Western-type high-fat and high-sugar diet
partially protected mice against influenza,
whereas artificially increasing BHB on a
normal diet was not protective. The KD
also differed from control diets in protein
content, which may independently affect
immune function11. Why do the effects
of the KD in VAT fade over time? Do the
pro-inflammatory consequences of obesity
swamp the effect of the KD, and how is
this balance struck? Or is the relevant
immunomodulatory mechanism of the
KD transient even if obesity is avoided?
Does this transience extend to the effect
of the KD on γδ T cells in the lung and
other tissues? The findings provide a
meaty new immune mechanism for the
nutritional regulation of metabolic disease
while leaving plenty of food for thought. ❐
Brianna J. Stubbs1 and John C. Newman   1,2*
1
Buck Institute for Research on Aging, Novato, CA,
USA. 2Division of Geriatrics, University of California
San Francisco, San Francisco, CA, USA.
*e-mail: jnewman@buckinstitute.org
Published online: 20 January 2020
https://doi.org/10.1038/s42255-019-0164-2
References
1. Rosen, E. D. & Spiegelman, B. M. Cell 156, 20–44 (2014).
2. Goldberg, E. L. et al. Nat. Metab. https://doi.org/10.1038/s42255-
019-0160-6 (2019).
3. Goldberg, E. L. et al. Sci. Immunol. 4, eaav2026 (2019).
4. Hallberg, S. J. et al. Diabetes Ther. 9, 583–612 (2018).
5. Moreno, B., Crujeiras, A. B., Bellido, D., Sajoux, I. &
Casanueva, F. F. Endocrine 54, 681–690 (2016).
6. Newman, J. C. & Verdin, E. Annu. Rev. Nutr. 37, 51–76 (2017).
7. Youm, Y. H. et al. Nat. Med. 21, 263–269 (2015).
8. Swanson, K. V., Deng, M. & Ting, J. P. Nat. Rev. Immunol. 19,
477–489 (2019).
9. Newman, J. C. et al. Cell Metab. 26, 547–557.e8 (2017).
10. Roberts, M. N. et al. Cell Metab. 26, 539–546.e5 (2017).
11. Weichhart, T., Hengstschläger, M. & Linke, M. Nat. Rev. Immunol.
15, 599–614 (2015).
Competing interests
J.C.N. is a co-founder with equity interest of BHB
Therapeutics Ltd., which is developing products related to
ketone bodies. B.J.S. has an equity interest in HVMN, Inc.,
which markets products related to ketone bodies, and
stock options in BHB Therapeutics Ltd. J.C.N. and B.J.S. are
co-inventors on patents related to the use of ketone bodies.