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.

The GnRH receptor (GnRHR), a member of the G protein-coupled receptor family, is a central regulator of reproductive function in all vertebrates. The peptide hormone GnRH exerts its effects via binding to the GnRHR in pituitary gonadotropes. We investigated the mechanisms of regulation of transcription of the mGnRHR gene in the mouse pituitary gonadotrope L beta T2 cell line by GnRH and dexamethasone (dex). Reporter assays with transfected mGnRHR promoter show that both dex and GnRH increase transcription of the mGnRHR gene via an activating protein-1 (AP-1) site. Real-time PCR confirmed this on the endogenous mGnRHR gene, and small interfering RNA experiments revealed a requirement for the glucocorticoid receptor (GR) for both the dex and GnRH response. Chromatin immunoprecipitation (ChIP) and immunofluorescence assays provide evidence that both GnRH and dex up-regulate the GnRHR gene via nuclear translocation and interaction of the GR with the AP-1 region on the mGnRHR promoter. We show that GnRH activates the unliganded GR by rapid phosphorylation of the GR at Ser-234 in a GnRHR-dependent fashion to transactivate a GRE reporter gene in L beta T2 and COS-1 cells. Using kinase inhibitors, we established a direct link between GnRH-induced protein kinase C and MAPK activation, leading to unliganded GR phosphorylation at Ser-234 and transactivation of the glucocorticoid response element. Furthermore, we show that GnRH and dex synergistically activate the endogenous GnRHR promoter in L beta T2 cells, via a mechanism involving steroid receptor coactivator-1 recruitment to the GnRHR AP-1 region. Our results suggest a novel mechanism of rapid nongenomic cross talk between the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes via GnRHR-dependent phosphorylation and activation of the unliganded GR in response to GnRH.

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Globally, the obesity pandemic is profoundly affecting quality of life and economic productivity, but efforts to address this, especially on a pharmacological level, have generally proven unsuccessful to date, serving as a stark demonstration that our understanding of adipocyte biology and pathophysiology is incomplete. To deliver better insight into adipocyte function and obesity, we need improved adipocyte models with a high degree of fidelity in representing the in vivo state and with a diverse range of experimental applications. Adipocyte cell lines, especially 3T3-L1 cells, have been used extensively over many years, but these are limited in terms of relevance and versatility. In this review, I propose that primary adipose-derived stromal/stem cells (ASCs) present a superior model with which to study adipocyte biology ex vivo. In particular, ASCs afford us the opportunity to study adipocytes from different, functionally distinct, adipose depots and to investigate, by means of in vivo/ex vivo studies, the effects of many different physiological and pathophysiological factors, such as age, body weight, hormonal status, diet and nutraceuticals, as well as disease and pharmacological treatments, on the biology of adipocytes and their precursors. This study will give an overview of the characteristics of ASCs and published studies utilizing ASCs, to highlight the areas where our knowledge is lacking. More comprehensive studies in primary ASCs will contribute to an improved understanding of adipose tissue, in healthy and dysfunctional states, which will enhance our efforts to more successfully manage and treat obesity.

Diet-induced obesity (DIO) in laboratory rodents can serve as a model with which to study the pathophysiology of obesity, but obesogenic diets (high-sugar and/or high-fat) are often poorly characterised and simplistically aimed at inducing metabolic derangements for the purpose of testing the therapeutic capacity of natural products and other bioactive compounds. Consequently, our understanding of the divergent metabolic responses to different obesogenic diet formulations is limited. The aim of the present study was to characterise and compare differences in the metabolic responses induced by low-fat, medium-fat/high-sugar and high-fat diets in rats through multivariate statistical modelling. Young male Wistar rats were randomly assigned to CON (laboratory chow, low-fat), OB1 (high-sugar, medium-fat) or OB2 (high-fat) dietary groups (n = 24 each) for 17 weeks, after which metabolic responses were characterised. Projection-based multivariate analyses (principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA)) were used to explore the associations between measures of body composition and metabolism. Furthermore, we conducted a systematic literature survey to examine reporting trends in rat dietary intervention studies, and to determine how the metabolic responses observed in the present study compared to other recently published studies. The OB1 and OB2 dietary regimens resulted in distinct metabolic profiles, with OB1 characterised by perturbations in insulin homeostasis and adipose tissue secretory function, while OB2 was characterised by altered lipid and liver metabolism. This work therefore confirms, by means of direct comparison, that differences in dietary composition have a profound impact on metabolic and pathophysiological outcomes in rodent models of DIO. However, through our literature survey we demonstrate that dietary composition is not reported in the majority of rat dietary intervention studies, suggesting that the impact of dietary composition is often not considered during study design or data interpretation. This hampers the usefulness of such studies to provide enhanced mechanistic insights into DIO, and also limits the translatability of such studies within the context of human obesity.