To treat metabolic syndrome, fat tissue dysfunction should be corrected rather than controlling conventional risk factors such as hypertension, dyslipidemia, and diabetes mellitus. For this purpose, ...accumulating evidence suggests increasing plasma adiponectin levels can be a key treatment strategy, especially in setting of food or drug selection. Here we report that adipocyte precursors obtained from several sites of fat tissue, which we call Metabolic Stem Cells (MSC), could be used as a novel screening system to identify adiponectin enhancing drugs or food for individual patients. MSC were prepared from fat tissues collected from 29 patients. They were differentiated in cultures into mature adipocytes. The time course of adiponectin production was independent of the number of mature adipocytes and gradually decreased at 48 h after differentiation. Pioglitazone, a full PPARgamma agonist, stabilized adiponectin production at days 8-16 after differentiation, whereas telmisartan, a partial PPARgamma agonist, showed variable response. Dividing the adiponectin secretion of day 12 by that of day 10 provided an estimate of adiponectin-producing activity irrespective of the number of MSC-derived adipocytes in culture. Using this score of adiponectin-production activity, we successfully assessed 16 agents in a 96-well plate. The effect of each agent on adiponectin production showed a similar pattern, independent of the site of isolated adipose tissue. Our results show that MSC can be used as a tool for selecting drugs that enhance adiponectin-production activity.
Chronic pancreatitis is a chronic clinical disorder characterized by irreversible damage to the pancreas and the development of histologic evidence of inflammation and fibrosis, and eventually the ...destruction and permanent loss of exocrine and endocrine tissue. A nationwide survey in Japan revealed an increase in the total number of patients treated for chronic pancreatitis from 32 000 in 1994 to 42 000 in 1999. The overall prevalence and the incidence rate of chronic pancreatitis also increased, from 28.5 and 5.4, respectively, in 1994 to 32.91 and 5.77 per 100 000 population, respectively, in 1999. Diagnostic criteria for chronic pancreatitis in Japan were proposed by the Japan Pancreas Society in 1995 and revised in 2001. The criteria were established to rule out false-positive cases and to confidently diagnose definite and probable cases of chronic pancreatitis, and thus easily detect advanced chronic pancreatitis, but the criteria are unable to lead to the early diagnosis of chronic pancreatitis. Cancer is the major cause of death in patients with chronic pancreatitis in Japan (49.6% of all deaths in patients with chronic pancreatitis). Clarification of the mechanisms by which possible chronic pancreatitis progresses to probable or definite chronic pancreatitis, and to pancreatic cancer, is an important research goal. Because even chronic pancreatitis defined as irreversible appears to be reversible for some time in its clinical course, there is an urgent need to develop methods for diagnosing reversible chronic pancreatitis, and to prevent the transition from chronic pancreatitis to pancreatic cancer.
Smad6 is implicated in the inhibition of bone morphogenetic protein signalling. However, the function of Smad6 in the pancreas remains obscure.
To elucidate the unknown function of Smad6, we ...developed transgenic mice selectively expressing Smad6 in pancreatic acinar cells using a plasmid construct coding rat elastase 1 enhancer/promoter.
Smad6 transgenic mice had no specific distinguishing phenotype such as body weight, pancreatic wet weight and concentrations of pancreatic protein. However, Smad6 transgenic mice reacted to hyperstimulation by caerulein injection or a diet containing 0.5% ethionine. Maximal amylase release stimulated by CCK-8 was significantly decreased in Smad6 transgenic mice acini, and trypsin activities in transgenic mice acini were significantly increased after stimulation of CCK-8. There was no difference in effect of CCK-8 stimulation on the subsequent increase in intracellular free Ca2+ concentration (Ca2+(i)) between wild-type and transgenic mice acini. These findings suggest that reduced pancreatic enzyme secretion was caused by the disorder of its downstream signal transduction pathways in acinar cells. The amino acid sequence at the N-terminus of Smad6 was similar to that of synaptosome-associated protein (SNAP) 25 interacting protein, which plays an important role in regulating exocytosis of pancreatic enzymes in acinar cells. Pancreatic SNAP25 protein levels in transgenic mice were decreased after caerulein-induced pancreatitis.
These results suggest that elevated expression of Smad6 inhibits normal function of SNAP25-interacting protein and SNAP25, reduces amylase secretion in acinar cells, and increases the susceptibility of acinar cells to the onset of pancreatitis.
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