Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4(+) Foxp3(+) T regulatory (T(reg)) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these T(reg) cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties of T(reg) cells to inhibit elements of the metabolic syndrome may have therapeutic potential.

/pdf/lean-but-not-obese-fat-is-enriched-for-a-unique-population-3m8z5k5902.pdf

Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters

Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4(+) T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (CD4(+)GATA-binding protein-3 (GATA-3)(+)) and regulatory forkhead box P3 (Foxp3)(+) T cells. CD4(+) (but not CD8(+)) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T(H)2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')(2) fragment, reduces the predominance of T(H)1 cells over Foxp3(+) cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4(+) T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.

/pdf/normalization-of-obesity-associated-insulin-resistance-e9elz44pzt.pdf

Normalization of obesity-associated insulin resistance through immunotherapy.

Compared with bone marrow-derived mesenchymal stem cells, adipose tissue-derived stromal cells (ADSC) do have an equal potential to differentiate into cells and tissues of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle. However, the easy and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide a clear advantage. Since extensive reviews focusing exclusively on ADSC are rare, it is the aim of this review to describe the preparation and isolation procedures for ADSC, to summarize the molecular characterization of ADSC, to describe the differentiation capacity of ADSC, and to discuss the mechanisms and future role of ADSC in cell therapy and tissue engineering. An initial effort has also been made to differentiate ADSC into hepatocytes, endocrine pancreatic cells, neurons, cardiomyocytes, hepatocytes, and endothelial/vascular cells. Whereas the lineage-specific differentiation into cells of mesodermal origin is well understood on a molecular basis, the molecular key events and transcription factors that initially allocate the ADSC to a lineage-specific differentiation are almost completely unknown. Decoding these molecular mechanisms is a prerequisite for developing novel cell therapies.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2006-0589

Concise review: adipose tissue-derived stromal cells--basic and clinical implications for novel cell-based therapies.

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

/pdf/b-cells-promote-insulin-resistance-through-modulation-of-t-5b7eoa2nh9.pdf

B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies

OBJECTIVE— We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications.

RESEARCH DESIGN AND METHODS— Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses.

RESULTS— Frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12, coincident with increases in 1 ) depot weight; 2 ) AT macrophages (ATMΦs) expressing F4/80 and CD11c; 3 ) mRNA for tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4 ) insulin resistance. ATMΦs in crown-like structures surrounding dead adipocytes expressed TNF-α and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached ∼80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition, and accelerated hepatic macrosteatosis. By week 20, adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 ( r = −0. 85, P < 0.001). In iAT, adipocyte death was first detected at week 12 and remained ≤3%.

CONCLUSIONS— These results implicate depot-selective adipocyte death and MΦ-mediated AT remodeling in inflammatory and metabolic complications of murine obesity.

https://diabetes.diabetesjournals.org/content/diabetes/56/12/2910.full.pdf

Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2005.05.031

C. Segafredo

Papers

Adipose tissues as an ancestral immune organ: site-specific change in obesity.