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GPR41 is reportedly expressed in murine adipose tissue and mediates short chain fatty acid (SCFA)-stimulated leptin secretion by activating Galpha(i). Here, we agree with a contradictory report in finding no expression of GPR41 in murine adipose tissue. Nevertheless, in the presence of adenosine deaminase to minimise Galpha(i) signalling via the adenosine A1 receptor, SCFA stimulated leptin secretion by adipocytes from wild-type but not GPR41 knockout mice. Expression of GPR43 was reduced in GPR41 knockout mice. Acetate but not butyrate stimulated leptin secretion in wild-type mesenteric adipocytes, consistent with mediation of the response by GPR43 rather than GPR41. Pertussis toxin prevented stimulation of leptin secretion by propionate in epididymal adipocytes, implicating Galpha(i) signalling mediated by GPR43 in SCFA-stimulated leptin secretion., (Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Leptin concentrations are elevated in the majority of obese individuals raising the possibility that leptin resistance contributes to their obesity. Peripheral leptin administration for 48 h caused a several-fold increase in mRNA encoding the suppressors of cytokine signaling SOCS-3 and CIS in hypothalamus and peripheral tissues. Paradoxically, CIS and SOCS-3 mRNAs are also elevated in the leptin-deficient ob/ob mouse. Forced expression of CIS in insulinoma cells prevented transactivation mediated by leptin. Thus tissues continuously exposed to leptin and/or other factors associated with obesity accumulate excessive amounts of SOCS-3 and CIS which could provide a potential mechanism for leptin resistance.

Interleukin-1beta (IL-1beta) is a potent inflammatory cytokine involved in type 1 diabetes and acts through defined IL-1beta signaling pathways. In the present work we describe induction of DNA binding activity to signal transducer and activator of transcription (STAT) in response to IL-1beta in clonal insulin-secreting cells. Moreover, IL-1beta activates a short isoform of STAT-3 that potently stimulates transcription. Immunoprecipitation studies reveal an interaction between the activated STAT-3 and the IL-1 receptor accessory protein indicating an association between the two signaling pathways. This may be a novel point of transduction cross talk and an additional mechanism utilised by IL-1beta in the pancreatic beta-cell during the process of type 1 diabetes.

The ob gene product, leptin, causes significant and dose-dependent inhibition of basal and insulin-stimulated glycogen synthesis in isolated soleus muscle from ob/ob mice, and a smaller, non-significant inhibition in muscle from wild-type mice. Leptin had no inhibitory effect on glycogen synthesis in soleus muscle from the diabetic (db/db) mice, which lack the functional leptin receptor. The full-length leptin receptor (Ob-Rb), is expressed in soleus muscle of both ob/ob and wild-type mice, however with no detectable differences in expression level. These results suggest that hyperleptinaemia may attenuate insulin action on glucose storage in skeletal muscle.

The maximal activities of the key glycolytic enzymes hexokinase and 6-phosphofructokinase, were reduced in brown adipose tissue in db/db mice compared to their lean littermates. Treatment of db/db mice with the thermogenic beta-adrenoceptor agonist, BRL 26830, restored normoglycaemia. The only significant increase in activity of hexokinase and 6-phosphofructokinase in the BRL 26830-treated db/db mice occurred in brown adipose tissue where the total tissue activity increased 10- and 11-fold respectively. These changes together with increased 2-deoxyglucose uptake in vivo suggest that brown adipose tissue can play a quantitatively important role in the removal of glucose from the blood.