William F. Ferris

The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity

The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.

Selenium stimulates pancreatic beta-cell gene expression and enhances islet function

The present study investigated the role of selenium in the regulation of pancreatic beta‐cell function. Utilising the mouse beta‐cell line Min6, we have shown that selenium specifically upregulates Ipf1 (insulin promoter factor 1) gene expression, activating the −2715 to −1960 section of the Ipf1 gene promoter. Selenium increased both Ipf1 and insulin mRNA levels in Min6 cells and stimulated increases in insulin content and insulin secretion in isolated primary rat islets of Langerhans. These data are the first to implicate selenium in the regulation of specific beta‐cell target genes and suggest that selenium potentially promotes an overall improvement in islet function.

Thymocyte activation induces the association of the proto-oncoprotein c-cbl and ras GTPase-activating protein with CD5.

Studies of knockout mice indicate that the glycoprotein CD5, which is expressed on T cells, most thymocytes and a subset of B cells, down‐regulates TCR‐ and B cell receptor (BCR)‐mediated signaling. CD5 is associated with the TCR and BCR, and is phosphorylated on cytoplasmic tyrosine residues following antigen receptor ligation. Cross‐linking of CD5 or pervanadate stimulation of thymocytes induces the association of a 120‐kDa tyrosine‐phosphorylated protein with CD5. The proto‐oncoprotein c‐cbl associates with CD5 in pervanadate‐stimulated thymocytes, and reprecipitation analysis demonstrates that the major proportion of CD5‐associated pp120 is c‐cbl. The GTPase‐activating protein for ras (ras GAP), which is not tyrosine phosphorylated following CD5 cross‐linking, associates with CD5 in pervanadate‐stimulated thymocytes. Using tyrosine‐phosphorylated peptides we show that ras GAP interacts in an SH2‐mediated manner with the phosphorylated Y429SQP sequence of CD5. Both c‐cbl and ras GAP have been proposed to suppress receptor‐mediated signaling, and may contribute to CD5‐mediated suppression of TCR or BCR signaling.

Insulin resistance in the control of body fat distribution: a new hypothesis.

Obesity causes insulin resistance, which is a prime etiological factor for type 2 diabetes, dyslipidemia, and cardiovascular disease. However, insulin resistance may be a normal physiological response to obesity that limits further fat deposition and which only has pathological effects at high levels. The current hypothesis suggests that in obesity the initial deposition of triglycerides occurs in subcutaneous adipose tissue and as this increases in size insulin resistance will rise and limit further subcutaneous lipid accumulation. Triglycerides will then be diverted to the visceral fat depot as well as to ectopic sites. This leads to a substantial rise in insulin resistance and the prevalence of its associated disorders. Evidence supporting this hypothesis includes studies showing that in lean subjects the prime determinant of insulin resistance is BMI, that is, subcutaneous fat whilst in overweight and obese subjects it is waist circumference and visceral adiposity. It has also been shown that the metabolic syndrome suddenly increases in prevalence at high levels of insulin resistance and we suggest that this is due to the diversion of lipids from the subcutaneous to the visceral depot. This system may have functioned in our evolutionary past to limit excessive adiposity by causing lipid deposition to occur at a site that has maximal effects on insulin resistance but involves minimal weight gain.

The effect of abdominal obesity on insulin sensitivity and serum lipid and cytokine concentrations in African women

Objectives  Studies have shown clear associations of abdominal obesity with lipid and glucose metabolism and cytokine levels in a number of different population groups. However, no such studies have been performed in an African population in which visceral adipose tissue levels have been shown to be lower than in European subjects.

Determinants of bone marrow adiposity: The modulation of peroxisome proliferator-activated receptor-γ2 activity as a central mechanism

Although the presence of adipocytes in the bone marrow is a normal physiological phenomenon, the role of these cells in bone homeostasis and during pathological states has not yet been fully delineated. As osteoblasts and adipocytes originate from a common progenitor, with an inverse relationship existing between osteoblastogenesis and adipogenesis, bone marrow adiposity often negatively correlates with osteoblast number and bone mineral density. Bone adiposity can be affected by several physiological and pathophysiological factors, with abnormal, elevated marrow fat resulting in a pathological state. This review focuses on the regulation of bone adiposity by physiological factors, including aging, mechanical loading and growth factor expression, as well as the pathophysiological factors, including diseases such as anorexia nervosa and dyslipidemia, and pharmacological agents such as thiazolidinediones and statins. Although these factors regulate bone marrow adiposity via a plethora of different intracellular signaling pathways, these diverse pathways often converge on the modulation of the expression and/or activity of the pro-adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)-γ2, suggesting that any factor that affects PPAR-γ2 may have an impact on the fat content of bone.

Once fat was fat and that was that: our changing perspectives on adipose tissue.

Abstract Past civilisations saw excess body fat as a symbol of wealth and prosperity as the general population struggled with food shortages and famine. Nowadays it is recognised that obesity is associated with co-morbidities such as cardiovascular disease and diabetes. Our views on the roll of adipose tissue have also changed, from being solely a passive energy store, to an important endocrine organ that modulates metabolism, immunity and satiety. The relationship between increased visceral adiposity and obesity-related co-morbidities has lead to the recognition that variation in fat distribution contributes to ethnic differences in the prevalence of obesity-related diseases. Our current negative view of adipose tissue may change with the use of pluripotent adipose-derived stromal cells, which may lead to future autologous stem cell therapies for bone, muscle, cardiac and cartilage disorders. Here, we briefly review the concepts that adipose tissue is an endocrine organ, that differences in body fat distribution underline the aetiology of obesity-related co-morbidities, and the use of adipose-derived stem cells for future therapies.

Depot-specific differences in the insulin response of adipose-derived stromal cells.

Visceral adiposity is more strongly linked to insulin resistance than subcutaneous adiposity. High insulin levels can be mitogenic or adipogenic to adipocytes, but little is known regarding these effects of insulin on stromal cells from visceral and subcutaneous fat depots. Consequently, we measured adipogenesis and mitosis in response to elevated insulin levels in rat adipose-derived stromal cells (ADSCs) from visceral (perirenal) and subcutaneous depots. Insulin alone, at 10 microM, did not stimulate adipogenesis in naïve perirenal visceral (pvADSCs) or subcutaneous ADSCs (scADSCs), although a significant increase in proliferation occurred in both. Adipogenesis, induced using adipocyte differentiation medium (AM), resulted in greater lipid accumulation in pvADSCs, but the associated decrease in proliferation was less than in scADSCs. Omission of insulin from AM significantly reduced lipid accumulation in pvADSCs, but had little effect in scADSC, whilst proliferation was inhibited more in scADSCs than pvADSCs. Consequently, insulin is more lipogenic and less mitogenic in differentiating pvADSCs compared to scADSCs.

Depot-specific and hypercaloric diet-induced effects on the osteoblast and adipocyte differentiation potential of adipose-derived stromal cells.

Adipose-derived stromal cells (ADSCs) can be differentiated in vitro into several mesenchyme-derived cell types. We had previously described depot-specific differences in the adipocyte differentiation of ADSCs, and consequently we hypothesized that there may also be depot-specific differences in osteoblast differentiation of ADSCs. For this study, the osteoblast differentiation potential of rat subcutaneous ADSCs (scADSCs) and perirenal visceral ADSCs (pvADSCs) was compared. Osteoblast differentiation media (OM) induced markers of the osteoblastic phenotype in scADSCs, but not in pvADSCs. ADSCs harvested from rats with diet-induced visceral obesity (DIO) exhibited reduced osteoinduction, compared to lean controls, but adipocyte differentiation was not affected. Expression of the pro-osteogenic transcription factor Msx2 was significantly higher in naïve scADSCs from lean and DIO rats than in pvADSCs. Our findings indicate that ADSCs from different anatomical sites are uniquely pre-programmed in vivo in a depot-specific manner, and that diet-induced metabolic disturbances translate into reduced osteoblast differentiation of ADSCs.

Lipid accumulation and alkaline phosphatase activity in human preadipocytes isolated from different body fat depots

Abstract Background: Alkaline phosphatase (ALP) controls intracellular lipid accumulation in human preadipocytes, but it is not known whether ALP is expressed in all body fat depots, or whether it has a similar role at all sites. Design: Cross-sectional. Setting and subjects: Subjects undergoing breast reduction and abdominal fat biopsies operations at Charlotte Maxeke Johannesburg Academic Hospital. Outcome measures: This study compared intracellular lipid accumulation and ALP activity in the presence and absence of ALP inhibitors in preadipocytes that were obtained from different adipose depots. Abdominal and mammary gland preadipocytes were isolated from women and induced to differentiate in culture. ALP activity and intracellular lipid levels were measured at baseline and after 12 days of differentiation in the presence and absence of the ALP inhibitors, histidine and levamisole. Results: ALP activity was detected in nondifferentiated abdominal (134 ± 7.5 mU/mg protein) and mammary gland (136 ± 9.6 mU/mg protein) preadipocytes. Its activity had increased significantly (p-value < 0.0005 for both) by day 12 of differentiation (388 ± 55 for abdominal and 278 ± 28 mU/mg protein for mammary). Preadipocytes treated with histidine had lower fat accumulation (p-value < 0.0005) and ALP activity (p-value < 0.005) than nontreated cells on day 12, while those treated with levamisole had lower fat accumulation (p-value < 0.005), but elevated ALP activity (p-value < 0.05), compared to nontreated cells. Lipid accumulation (p-value < 0.005) and ALP activity (p-value < 0.05) were higher in abdominal than mammary gland preadipocytes by day 12. Conclusion: ALP is involved in the control of intracellular lipid accumulation in human preadipocytes that are isolated from both adipose depots. The ability of levamisole to inhibit this process while activating ALP, suggests that this molecule acts via an ALP-independent pathway, while histidine attenuates both lipid deposition and ALP activity.