Fat-loving Tregs control insulin sensitivity during ageing

I have noticed in the past couple of weeks that there is a surge of Foxp3⁺ T cell papers published in top journals. Just yesterday Nature published another paper where the authors claim that they have discovered ageing-related [separate] pathway of insulin resistance driven by fat-associated Tregs.

Lets review their claims. First, the authors showed that unlike "classical" obesity-driven insulin resistance, ageing-related insulin resistance is characterized by enrichment of Foxp3⁺ T cells in adipose tissue (visceral adipose tissue, VAT).

Next, the authors showed that selective depletion of fat Tregs in ageing Foxp3^cre PPARγ ^fl/fl mice promoted shift into "lean body" metabolism[selective decrease in fat mass].

This shift to lean body metabolism in fat Treg depleted mice [i.e. insulin sensitivity ↑] occurred in ageing mice, not in young or obese mice.

Finally, since most of fat Tregs were positive for surface ST2, a receptor for IL-33, their depletion in ageing mice with anti-ST2 antibody [not very efficient by the way] could still improve insulin sensitivity by 25% over control [without any overt inflammation].

In summary, this study uncovered a novel pathway of ageing-associated insulin resistance driven by ST2⁺ fat Tregs. This pathway differs from obesity-driven insulin resistance. However, it is important to remember here that B6 mice [used in this experiments] have strong tendency for obesity during ageing and it remains seen whether this phenomenon with fat Tregs will be applicable for other strains or for humans.

David Usharauli

IL-33 links innate lymphoid cells group 2 to lean body mass control

There is one aspect of immune system that I did not get at all. It is related to the role of immune system in maintaining a lean body mass by controlling browning [beiging] of white adipose tissue and increasing energy expenditure.

Previous studies have implicated immune cells, such as eosinophils, type 2 macrophages and IL-4rα signalling in body energy expenditure and lean body mass control. New study in journal Nature has provided evidence suggesting that type 2 innate lymphoid cells, ILC2 and IL-33 play an independent and non-redundant role in lean body mass control and energy expenditure. 

The authors showed that in both human and mouse, white adipose tissue contain Lin^- IL-25⁺ IL-127⁺population expressing IL-33R typical for ILC2. The frequency and number of ILC2 population in white adipose tissue were inversely correlated with obesity or high fat diet.

Experiments with IL-33KO mice or recombinant mouse IL-33 showed that ILC2 population in white adipose tissue retracted or expanded depending on presence of IL-33.

Adipose tissue analysis revealed that IL-33 induced UCP1 expression in white adipose tissue. UCP1 is responsible for high energy expenditure in beige fat.

Adoptive transfer of ILC2 into ILC2-deficient hosts showed that IL-33 worked through ILC2. Additional experiments revealed that IL-33/ILC2 axis worked independently from eosinophils, regulatory T cells or IL-4rα signalling.

Somewhat similar results were presented in another paper published in journal Cell earlier this year. However, in that paper the authors observed that eosinophils and IL-4rα signalling were also involved alongside with IL-33/ILC2. It would be interesting to know what is the reason for this discrepancy.

In summary, these results points to a novel function of innate immune system. Though It may even nothing to do with immune function per se but rather linking ancient metabolic pathways to innate immune cells. Even if IL-33 can help to reduce body fat, it does not necessarily means that we could start injecting obese people with IL-33. IL-33 has been implicated in pathological responses as well, like asthma or allergy. Only global view of cytokine function could tell us the real usefulness of any finding. Discrete, individual disease models are insufficient for this task and could lead to wrong conclusions. 

David Usharauli

NK cell activation initiates type II diabetes

Type II diabetes is a complex syndrome involving endocrine, immune and metabolic abnormalities. It is well known that obesity can lead to type II diabetes. But how?

New study in Nature Immunology suggests that obesity-induced adipocyte stress activates NK cells  via NCR1 receptor driving IFN-γ mediated insulin insensitivity characteristic to type II diabetes.

The authors observed that NK cell depletion in mice fed high fat diet (HFD) ameliorated insulin insensitivity and glucose intolerance.

Ex vivo examination of visceral adipose tissue (VAT), a target tissue of type II diabetes, revealed that HFD induced expression of NK cell ligand in VAT detected by NCR1 (NKp46 in humans).

Interestingly, VAT but not subcutaneous (Sc fat) adipose tissue from HFD fed mice could stimulate NK cells.

In vivo experiments confirmed that NCR1 deficiency improved insulin sensitivity.

Finally, the authors showed that IFN-γ derived from NCR1 activated NK cells promotes inflammatory macrophages in VAT leading to glucose intolerance, that can be ameliorated with NCR1 blockade.

In summary, these results showed that HFD induces visceral adipose tissue stress that activates local NK cells via NCR1 ligand leading to inflammatory macrophage polarization and reduced insulin sensitivity. Targeting NK cell activation may interrupt this disease cycle and improve type II diabetes management.

I was always wondered why diet-induced obesity leading to VAT stress should activate inflammatory, M1 type macrophages? What is an evolutionary advantage for such response, in general? No idea.  

David Usharauli