Obesity: Mak TW

Yuen YP, Lai CK, Poon WT, Ng SW, Chan AY, Mak TW. · Department of Pathology, Princess Margaret Hospital, Laichikok, Kowloon, Hong Kong. · Hong Kong Med J. · Pubmed #17548910 links to  free full text

Abstract: OBJECTIVES: To review pharmaceutical analogue adulteration of non-prescription slimming products. DESIGN: Retrospective study. SETTING: Tertiary referral centre for toxicology analysis, Hong Kong. PATIENTS: All patients known to have been hospitalised after taking slimming products adulterated with pharmaceutical analogues from September 2004 to December 2006. MAIN OUTCOME MEASURES: Age, reasons for hospital admission, major biochemical findings, and toxicology analysis results of the offending slimming products. RESULTS: N-nitrosofenfluramine, an analogue of fenfluramine with hepatotoxic effect, was found in two slimming products. Three patients were hospitalised after taking these slimming products, one of whom developed liver failure treated by liver transplantation. Another slimming product was found to contain N-desmethyl-sibutramine, an analogue of sibutramine. A patient with an unremarkable medical history developed acute psychosis after taking the latter product for 1 week. CONCLUSIONS: Analogues, created by modifying the chemical structures of pharmaceuticals, are used as adulterants in non-prescription slimming products, in an attempt to evade regulatory inspection. The imperceptible use of these analogues is very dangerous because they have not been tested formally for efficacy and safety. In view of the potential harm to the public, more effective and proactive measures are required to guard against the illicit use of pharmaceutical analogues. There is also a need for increased awareness among the public and the medical professionals about this emerging threat.

Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Münzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, Brüning JC. · Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne (CMMC), Cologne, Germany. · J Clin Invest. · Pubmed #16794735 links to  free full text

Abstract: Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.

Komazawa N, Matsuda M, Kondoh G, Mizunoya W, Iwaki M, Takagi T, Sumikawa Y, Inoue K, Suzuki A, Mak TW, Nakano T, Fushiki T, Takeda J, Shimomura I. · Department of Social and Environmental Medicine, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, Osaka, Japan. · Nat Med. · Pubmed #15489860 No free full text.

Abstract: Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.