High Fat Diet Rapidly Suppresses B Lymphopoiesis by Disrupting the Supportive Capacity of the Bone Marrow Niche

Abstract

The bone marrow (BM) niche is the primary site of hematopoiesis, and cues from this microenvironment are critical to maintain hematopoiesis. Obesity increases lifetime susceptibility to a host of chronic diseases, and has been linked to defective leukogenesis. The pressures obesity exerts on hematopoietic tissues led us to study the effects of a high fat diet (HFD: 60% Kcal from fat) on B cell development in BM. Seven week old male C57Bl/6J mice were fed either a high fat (HFD) or regular chow (RD) diet for periods of 2 days, 1 week and 6 weeks. B-cell populations (B220+) were not altered after 2 d of HFD, within 1 w B-cell proportions were reduced by −10%, and by 6 w by −25% as compared to RD (p<0.05). BM RNA was extracted to track the expression of B-cell development markers Il-7, Ebf-1 and Pax-5. At 2 d, the expression of Il-7 and Ebf-1 were reduced by −20% (p = 0.08) and −11% (p = 0.06) whereas Pax-5 was not significantly impacted. At one week, however, the expressions of Il-7, Ebf-1, and Pax-5 in HFD mice fell by -19%, −20% and −16%, and by six weeks were further reduced to −23%, −29% and −34% as compared to RD (p<0.05 for all), a suppression paralleled by a +363% increase in adipose encroachment within the marrow space (p<0.01). Il-7 is a critical factor in the early B-cell lineage which is secreted by supportive cells in the BM niche, and is necessary for B-cell commitment. These data indicate that BM Il-7 expression, and by extension B-cell differentiation, are rapidly impaired by HFD. The trend towards suppressed expression of Il-7 following only 2 d of HFD demonstrates how susceptible the BM niche, and the cells which rely on it, are to diet, which ultimately could contribute to disease susceptibility in metabolic disorders such as obesity.

Inhibition of B Lymphopoiesis by Adipocytes and IL-1–Producing Myeloid-Derived Suppressor Cells

“…B-lymphopoiesis may also be regulated by caloric restriction. Similar to thymic atrophy, high fat diet results in increased adipose tissue in the BM and decreased B-lymphopoiesis in young adult mice (25). Further, obese mice have decreased BM lymphoid multipotent progenitors and CLPs (71).…”

“…Adipose tissue is a source of “lipotoxic” danger signals that result in inflammation (23), and this sterile inflammation leads to decreased T-lymphopoiesis. Changes in hematopoiesis are also observed in obesity, as evidenced by increased myelopoiesis in obese mice (24), and increased myelopoiesis as well as decreased B-lymphopoiesis in mice fed a high fat diet (25). …”

Immuno-metabolism and adipose tissue: The key role of hematopoietic stem cells

“…Only a few studies have studied the effect of high fat diet (HFD)-induced obesity on hematopoietic process, with conflicting results, although an increase of BM adiposity is clearly described. Both rapid dysregulation of B-cell populations that results from diminished cellular differentiation [61] and enhancement of hematopoiesis and lymphopoiesis [62] are reported, but these studies differ by the diet protocol. Consistent with data on ob/ob mice, leukocytosis and neutrophilia have also been described in HFD-rodents together with a granulopoiesis in the BM due to an increase in G-CSF production by stromal cells [60,63,64].…”

Bone marrow fat and the decline of B lymphopoiesis in rabbits

“…Some of these include accumulation of adipocytes in the BM (Adler et al, 2014, Chinn et al, 2012, Justesen et al, 2001, Rosen et al, 2009) and thymus (Yang et al, 2009a, 2009b), increased systemic inflammation (Baylis et al, 2013, Nagareddy et al, 2014, Osborn and Olefsky, 2012, Vasto et al, 2007), and reduced B and T lymphopoiesis. Elegant studies by Dixit and colleagues linked these phenotypes in the context of thymic involution and decreased T lymphopoiesis in mice (Yang et al, 2009a, 2009b, Youm et al, 2012).…”

“…Thymic decline is accelerated by a high fat diet (Yang et al, 2009b), and decelerated by calorie restriction (Yang et al, 2009a), suggesting that adipocyte products and diet affect this process. In the context of B lymphopoiesis, Adler et al (2014) found that a high fat diet increased BM adiposity in as little as 6weeks, and resulted in decreased B lymphopoiesis. These studies suggest that calorie restriction may lead to increased B lymphopoiesis.…”