Metabolism

Inflammation keeps old mice healthy

Immune cells called regulatory T cells accumulate in fat during ageing. The anti-inflammatory activity of these cells worsens age-associated defects in metabolism, in contrast to its effect in obesity. See Letter p.137

Body fat undergoes extensive and frequent remodelling, as changes in blood-vessel development, connective tissue, the number and size of fat cells, and other features allow fat to store or release the energy that the organism needs. But this adaptive process can become harmful in stressful conditions. Maladaptive remodelling in obese rodents and humans is associated with larger fat cells and chronic inflammation in fat, leading to insulin resistance, type 2 diabetes and cardiovascular complications1. Attempts to disentangle the various components that cause this dysregulation of metabolism have revealed a coordinated inflammatory circuit involving interactions between several cell types1. On page 137 of this issue, Bapat et al.2 add a new twist to the story, providing evidence that, contrary to what might be expected, age-associated metabolic changes may be regulated by a different mechanism from those associated with obesity.

Specialized immune cells called regulatory T cells (Treg cells) suppress the inflammatory immune responses driven by white blood cells. The importance of Treg cells for the functioning of the immune system is highlighted by the fact that mammals that lack the transcription factor FOXP3 — which controls the development, maintenance and function of Treg cells — develop multi-organ autoimmune disease. Although many different immune cells are present in fat, fat-resident Treg cells (fTreg cells) have attracted attention as potential modulators of local inflammation3,4.

The Treg cells first enter fat immediately after birth, accumulate during ageing and acquire a molecular signature characterized by the expression of several factors5,6,7,8, including the transcription factor PPAR-γ, which controls differentiation, and the protein subunit ST2 (a receptor for the protein IL-33), which has been implicated in the development of fTreg cells. Furthermore, some T-cell-receptor proteins (which recognize structures called antigens during an immune response) are preferentially expressed in fTreg cells over other Treg cells, suggesting that certain fTreg populations proliferate in response to antigens3,4,5. Although much remains to be learnt, data from animal models of obesity suggest that fTreg cells protect against inflammation and metabolic dysfunction3,5,6,7,8.

Bapat et al. analysed fTreg cells in ageing mice, rather than in models of obesity, and turned the tables on previous assumptions about these cells. Understanding ageing-associated metabolic dysregulation is vital, because age is a major risk factor for insulin resistance and diabetes. The authors observed a striking age-related accumulation of fTreg cells. But unexpectedly, when the authors depleted the fTreg population by deleting PPAR-γ in these cells, they found that the ageing mutant mice gained less weight than their wild-type counterparts — they accumulated less body fat and more lean weight, ate more and burnt more calories than age-matched controls.

Every metabolic parameter analysed by the authors was better in these mice. Fasting glucose and insulin levels decreased, as did insulin resistance. By contrast, pharmacological expansion of the fTreg population increased levels of insulin resistance and other parameters of metabolic dysregulation.

The researchers found that fTreg depletion was associated with increased local levels of the pro-inflammatory signalling molecule TNF-α, consistent with increased fat inflammation. Depletion was also correlated with a reduction in fat-cell size and with reduced expression of collagen genes — evidence of improved metabolic activity and beneficial fat remodelling. Ageing fTreg cells maintained their molecular signature and their ability to suppress immune responses, indicating that their function had not been subverted. Together, these data demonstrate that fTreg accumulation plays a part in age-associated metabolic dysregulation, and that at least some aspects of the inflammatory response suppressed by fTreg cells are favourable in ageing (Fig. 1).

Figure 1: Regulatory T cells impair metabolic regulation in old fat.
figure1

a, During ageing, immune cells called fat-resident regulatory T (fTreg) cells accumulate in body fat and decrease local inflammation (red colouring). This age-associated accumulation correlates with increases in metabolic dysregulation and in the size of the fat cells, and with a decrease in the ability of fat to remodel — the process by which fat undergoes morphological alterations in response to changing nutrient demands. b, Bapat et al.2 depleted the fTreg population in ageing mice. This increased inflammation, reduced the size of fat cells and improved fat remodelling, thereby improving metabolic regulation.

These surprising results contrast with previous observations, which indicated that fTreg numbers decrease in obese mice, and that fTreg expansion improves metabolic health without affecting weight3,5,6,7,8. Although Bapat et al. focused on ageing, some of their results are notably divergent from previous data. For instance, the authors found no evidence that fTreg cells modulate metabolism in a high-fat-diet model of obesity (although there were few fTreg cells in the fat, and the consequences of expanding the fTreg population were not tested in this model). Directly contradicting previous data7, they found that stimulating PPAR-γ activity with the antidiabetic drug rosiglitazone exerted beneficial metabolic effects in obese mice, even those in which PPAR-γ was deleted in fTreg cells, suggesting that other cell types are crucial targets for this drug.

The reasons for these discrepancies remain to be investigated. Perhaps they represent differences in experimental design, or in the populations of commensal bacteria found in mice used at different institutions. It will also be essential to evaluate whether the effects of fTreg cells observed in mice apply to humans. A complicating factor is that ageing- and obesity-associated metabolic dysregulation often coexist in humans.

Nonetheless, information is accumulating about fTreg cells and inflammation. First, other laboratories have also detected age-dependent Treg accumulation in fat6,9, although the metabolic impact of fTreg cells in ageing has not previously been measured. Second, a refined understanding of the cells' gene-expression profile is emerging, providing hints about their molecular regulation and tools that could be used to manipulate their numbers and function3,6,7,8. Third, compelling evidence3,5 supports the existence of antigens in fat that drive expansion of fTreg populations; these are probably presented to fTreg cells in association with the antigen-presenting protein complex, major histocompatibility complex class II. It will be crucial to identify these antigens and other factors that contribute to fTreg accumulation during ageing.

Is there crosstalk between fTreg cells and other immune cells, such as innate lymphoid cells (ILCs)? Recent reports10,11 have shown that ILCs infiltrate fat, and have indicated that IL-33 activates ILC2s to induce white fat to become heat-producing beige fat. It is possible that IL-33 has two opposing roles: inducing energy expenditure through ILC2s, but ensuring energy conservation through expansion of the fTreg population and by inducing the secretion of molecules such as IL-10 that promote anabolic activity (which increases energy storage in fat)12. Thus, fTreg depletion could tip the balance in favour of energy expenditure, causing weight loss and improved metabolic health. However, so far there have been no studies on IL-33 or ILC2s in ageing mice.

Finally, blocking inflammatory pathways in ageing fat cells has been reported to impair metabolic regulation13, in contrast to the prevailing view but consistent with Bapat and colleagues' data. Identifying beneficial elements of the inflammatory response, and investigating their metabolic effects, will be essential, and may point to evolutionarily conserved features of inflammation that lead to tissue adaptation under abnormal conditions. In fat and elsewhere, different facets of inflammation might have many roles, both good and bad.Footnote 1

Notes

  1. 1.

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Correspondence to Ivan Maillard or Alan R. Saltiel.

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Maillard, I., Saltiel, A. Inflammation keeps old mice healthy. Nature 528, 44–46 (2015). https://doi.org/10.1038/nature15648

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