The effects of a green Rooibos (Aspalathus linearis) extract on metabolic parameters and adipose tissue biology in rats fed different obesogenic diets.

Current pharmaceutical treatments addressing obesity are plagued by high costs, low efficacy and adverse side effects. Natural extracts are popular alternatives, but evidence for their anti-obesity properties is scant. We assessed the efficacy of a green (minimally-oxidized) Rooibos (Aspalathus linearis) extract (GRT) to ameliorate the effects of obesogenic feeding in rats, by examining body weight, metabolic measures, adipose tissue cellularity and tissue-resident adipose stem cells (ASCs). Furthermore, we performed statistical correlations to explore the relationships and interactions between metabolic and adipose tissue measures. Using an in vivo/ex vivo study design, male Wistar rats were maintained for 17 weeks on one of 3 diets: CON (laboratory chow), OB1 (high-sugar, medium fat) or OB2 (high-fat, high-cholesterol) (n = 24 each). From weeks 11-17, half of the animals in each group received oral GRT supplementation (60 mg per kg body weight daily). Blood and tissue samples were collected, and ASCs from each animal were cultured. Diets OB1 and OB2 induced divergent metabolic profiles compared to CON, but metabolic measures within dietary groups were mostly unaffected by GRT supplementation. Notably, diets OB1 and OB2 uncoupled the positive association between visceral adiposity and insulin resistance, while GRT uncoupled the positive association between elevated serum cholesterol and liver damage. Obesogenic feeding and GRT supplementation induced adipocyte enlargement in vivo, but lipid accumulation in cultured ASCs did not differ between dietary groups. Larger adipocyte size in subcutaneous fat was associated with favourable glucose metabolism measures in all GRT groups. In conclusion, GRT affected the associations between systemic, adipose tissue-level and cellular measures against the background of obesogenic diet-induced metabolic dysregulation.

BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory.

BACE inhibitors, which decrease BACE1 (ß-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer's disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function. Mice were treated with an in-diet BACE inhibitor for 4-8 weeks to achieve a clinically-relevant level of amyloid-ß40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins. Wild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light-dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. Chronic BACE inhibition for 1-2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.

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.

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.

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.

Activation of the cannabinoid 2 (CB2) receptor inhibits murine mesenteric afferent nerve activity.

Abstract Cannabinoid 2 (CB2) receptors have both antinociceptive and antihypersensitivity effects, although the precise mechanisms of action are still unclear. In this study, the modulatory role of CB2 receptors on the mesenteric afferent response to the endogenous immunogenic agent bradykinin (BK) was investigated. Mesenteric afferent recordings were obtained from anaesthetized wild-type and CB2(-/-) mice using conventional extracellular recording techniques. Control responses to BK were obtained in all experiments prior to administration of either CB2 receptor agonist AM1241, or AM1241 plus the CB2 receptor antagonist AM630. Bradykinin consistently evoked activation of mesenteric afferents (n = 32). AM1241 inhibited the BK response in a dose dependent manner. In the presence of AM630 (10 mg kg(-1)), however, AM1241 (10 mg kg(-)1) had no significant effect on the BK response. Moreover, AM1241 had also no significant effect on the BK response in CB2(-/-) mice. Activation of the CB2 receptor inhibits the BK response in mesenteric afferents, demonstrating that the CB2 receptor is an important regulator of neuroimmune function. This may be a mechanism of action for the antinociceptive and antihypersensitive effects of CB2 receptor agonists.