Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss

The prevalence of obesity has continued to rise over the past three decades leading to significant increases in obesity-related medical care costs from metabolic and non-metabolic sequelae. It is now clear that expansion of body fat leads to an increase in inflammation with systemic effects on metabolism. In mouse models of diet-induced obesity there is also an expansion of bone marrow adipocytes. However, the persistence of these changes after weight-loss has not been well described. The objective of this study was to investigate the impact of high-fat diet (HFD) and subsequent weight-loss on skeletal parameters in C57Bl6/J mice. Male mice were given a normal chow diet (ND) or 60% HFD at 6-weeks of age for 12-, 16-, or 20-weeks. A third group of mice was put on HFD for 12-weeks and then on ND for 8-weeks to mimic weight-loss. After these dietary challenges the tibia and femur were removed and analyzed by microCT for bone morphology. Decalcification followed by osmium staining was used to assess bone marrow adiposity and mechanical testing was performed to assess bone strength. After 12-, 16-, or 20-weeks of HFD, mice had significant weight gain relative to controls. Body mass returned to normal after weight-loss. Marrow adipose tissue (MAT) volume in the tibia increased after 16-weeks of HFD and persisted in the 20-week HFD group. Weight loss prevented HFD-induced MAT expansion. Trabecular bone volume fraction, mineral content, and number were decreased after 12-, 16-, or 20-weeks of HFD, relative to ND controls, with only partial recovery after weight-loss. Mechanical testing demonstrated decreased fracture resistance after 20-weeks of HFD. Loss of mechanical integrity did not recover after weight-loss. Our study demonstrates that HFD causes long-term, persistent changes in bone quality, despite prevention of marrow adipose tissue accumulation, as demonstrated through changes in bone morphology and mechanical strength in a mouse model of diet-induced obesity and weight-loss

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes

Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages

Obesityâ related changes in adipose tissue leukocytes, in particular adipose tissue macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white adipose tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3â 56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation. ATMs, ATDCs, and ECs increased with rapid WAT expansion, with ATMs derived primarily from a CCR2â independent resident population. WAT expansion stimulated proliferation in resident ATMs and ECs, but not CD11c+ ATMs or ATDCs. ATM proliferation was unperturbed in Csf2â and Rag1â deficient mice with WAT expansion. Additionally, ATM apoptosis decreased with WAT expansion, and proliferation and apoptosis reverted to baseline with weight loss. Adipocytes reached maximal hypertrophy at 28 days of HFD, coinciding with a plateau in resident ATM accumulation and the appearance of lipidâ laden CD11c+ ATMs in visceral epididymal WAT. ATM increases were proportional to tissue expansion and adipocyte hypertrophy, supporting adipocyteâ mediated regulation of resident ATMs. The appearance of lipidâ laden CD11c+ ATMs at peak adipocyte size supports a role in responding to ectopic lipid accumulation within adipose tissue. In contrast, ATDCs increase independently of proliferation and may be derived from circulating precursors. These changes precede and establish the setting in which largeâ scale adipose tissue infiltration of CD11c+ ATMs, inflammation, and adipose tissue dysfunction contributes to insulin resistance.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142947/1/jlb10097_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142947/2/jlb10097.pd

Weight Regain in Formerly Obese Mice Hastens Development of Hepatic Steatosis Due to Impaired Adipose Tissue Function

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155467/1/oby22788-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155467/2/oby22788_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155467/3/oby22788.pd

The molecular mechanisms of Foxp3 gene regulation.

Induction of Foxp3 gene expression and acquisition of regulatory T cell fate is, understandably, a highly controlled process and one which many investigators want to illuminate. In studying the regulation of Foxp3 gene expression, several conserved non-coding regions have been identified and the role of various transcription factors at these sites has been explored. What emerges is that many factors, some positive, some negative, interact to collectively drive Foxp3 gene expression and then maintain its expression in Foxp3(+) regulatory T cells. TCR signaling is imperative for Foxp3 gene expression and TGF-β is a key cytokine for initiating Foxp3 gene expression in naïve T cells. But other signaling pathways are also known to play a role in properly orchestrating Foxp3 gene expression and regulatory T cell expansion. Here we review the recent progress in understanding the complex molecular events that drive Foxp3 gene expression and allow functional regulatory T cells to develop

Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice

Objective: In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. Methods: We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. Results: We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c− macrophages, increased frequencies of T cells (CD4+, CD8+, and CD4−/CD8− T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. Conclusions: These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss. Author Video: Author Video Watch what authors say about their articles Keywords: Sleeve gastrectomy, Adipose tissue, Macrophages, T cells, Dendritic cells, Abbreviations: ATDC, adipose tissue dendritic cell, ATM, adipose tissue macrophage, eWAT, epididymal white adipose tissue, FFA, free fatty acids, HFS, high fat sham, iWAT, inguinal white adipose tissue, SVC, stromal vascular cells, VSG, vertical sleeve gastrectom

Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β.

The molecular mechanisms directing the development of TCRαβ(+)CD8αα(+) intestinal intraepithelial lymphocytes (IEL) are not thoroughly understood. Here we show that transforming growth factor-β (TGF-β) controls the development of TCRαβ(+)CD8αα(+) IEL. Mice with either a TGF-β1 null mutation or a T cell-specific deletion of the TGF-β receptor I lacked TCRαβ(+)CD8αα(+) IEL, whereas transgenic mice that over-expressed TGF-β1 had an increased population of TCRαβ(+)CD8αα(+) IEL. Defective development of the TCRαβ(+)CD8αα(+) IEL thymic precursors (CD4(-)CD8(-)TCRαβ(+)CD5(+)) was observed in the absence of TGF-β. In addition, we showed that TGF-β signaling induced CD8α expression in TCRαβ(+)CD8αα(+) IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. These data demonstrate a previously unrecognized role for TGF-β in the development of TCRαβ(+)CD8αα(+) IEL and the expression of CD8 in T cells