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Does Altered Immune Function Cause Obesity?



sharma-obesity-adipose-tissue-macrophageThe role of proinflammatory cells in adipose tissue as a determinant of insulin resistance and altered metabolic function is now well known.

However, there is also new data suggesting that altered immune function may well be an important causal step in the accumulation of excess fat and related metabolic abnormalities.

Two studies, both in animal models, point to a role of perforin, a cytotoxic effector molecule primarily released by CD8+ T cells and natural killer (NK) cells to eliminate infected or dangerous cells via the perforin-granzyme cell death pathway. In rare cases of humans with impaired perforin-dependent cytotoxic function, one often sees excessive T-cell activation, severe hyper-inflammation and possibly death.

The first study by Xavier Revelo and colleagues from the University of Toronto, published in Diabetes, perforin-deficient mice (Prf1null), which show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD) were shown to have an increased accumulation of proinflammatory IFN-γ–producing CD4+ and CD8+ T cells and M1-polarized macrophages in visceral adipose tissue.

Furthermore, transfer of CD8+ T cells from Prf1null mice into CD8-deficient mice (CD8null) resulted in worsening of metabolic parameters compared with wild-type donors, thus demonstrating a role for T-cell function in insulin resistance associated with visceral adipose tissue.

In a second independent study by Yael Zlotnikov-Klionsky and colleagues from the Weizmann Institute of Science in Rehovot, Israel, published in Immunity, showed that animals selectively lacking perforin-rich granules in their dendritic cells, progressively gained weight and exhibited features of metabolic syndrome, an effect that could be completely prevented by T cell depletion.

Both studies show that the immunoregulatory protein perforin appears to be an important regulator or body weight and metabolic function – a finding, which may well open a new door biological drivers of obesity.

Incidentally, perforin also plays a role in auto-immune diseases and this finding may thus provide a link between the common occurrence of obesity in people with auto-immune disease and has led some authors to even suggest that obesity itself may be a form of auto-immune disease.

While the therapeutic options will certainly not be as simple as replacing low levels of perforin, understanding exactly how immune function ties into the regulation of body weight may eventually lead to novel targets.

@DrSharma
Edmonton, AB

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