ob/ob mouse Science 1996 December 6; 274: 1704-1707. Science 1996 December 6; 274: 1704-1707.
Science 1996 December 6; 274: 1704-1707.
Fig. 1. Physical appearance and body weights of normal (OB/OB), ob/ob, and NPY/ ob/ob mice. (A) Representative body shapes of male mice at 15 weeks of age. Photo was cropped at mid-tail level. (B and C) Body weights of male and female mice at various ages. Values are the mean ± SEM; n > 10 for each group.
Body weight of NPY/ ob/ob females was significantly lower than that of ob/ob females at all ages after 6 weeks (P < 0.01). Body weight of NPY/ ob/ob males was significantly lower than that of ob/ob males at all ages after 10 weeks (P < 0.02).
Fig. 2. Adiposity of normal, ob/ob, and NPY/ ob/ob mice. (A) Fat-selective magnetic resonance images (MRIs) of male mice at 14 weeks of age (12). Images are 3-mm thick, body length, horizontal sections. Adipose tissue appears white. Images are oriented such that the head of each mouse is at the top. The sides of the ob/ob image are straight because the mouse was pressed against the walls of the MR tube.
(B) Average lipid:water ratios of 12- to 15-week-old mice obtained from MR spectra (12). Values are the mean ± SEM. Each group consisted of four males and three females. *P < 0.001 compared to ob/ob mice; unpaired t-test. Some ob/ob mice, but not double mutants, could not be analyzed by this technique because they were too large to fit into the 4.2-cm-diameter coil. Consequently, the adiposity of ob/ob mice was slightly underestimated. (C) Combined weights of inguinal, retroperitoneal, scapular, and reproductive pads, measured when mice were 16 weeks of age. Values are the mean ± SEM. The ob/ob group consisted of 19 males and 15 females; the double mutant group consisted of 12 males and 10 females. **P < 0.001 compared to ob/ob mice, unpaired t-test.
A 32 000 molecular weight uncoupling protein (now termed uncoupling protein-1, or UCP1) located in the inner mitochondrial membrane of BAT. UCP1, which exists in active and inactive forms, is unique to brown fat and as such differentiates the two forms of adipose tissue (brown and white); it also appears to be restricted to mammals. A family of mammalian uncoupling proteins has now been identified – UCP1, UCP2, UPC3, BMCP1 (and perhaps UCP4) – with homologues in birds and plants. UCP2 has a wide tissue
distribution, but is found particularly in white adipose tissue and cells of the immune system, while UCP3 is primarily expressed in skeletal muscle. Although these proteins were initially thought to act as uncouplers in a manner analogous to UCP1, it is increasingly clear that this is not the case. UCP2 and UCP3 may in practice be involved in lipid oxidation or play a role in antioxidant defence. A role for UCP1 and for brown adipose tissue as a locus for adaptive thermogenesis in relation to energy balance, as well as in thermoregulation, in rodents is well established. However, the extent to which brown fat thermogenesis normally occurs in adult humans remains problematic. Nevertheless,
UCP1 is present in certain adipose tissue depots throughout life and increased levels (indicating activation of brown fat) are evident in patients with pheochromocytoma.
Research Symposium – Human Energy Metabolism J Physiol (2003) 547.S Paul Trayhurn
The seminal proposal by Steppan et al. suggested resistin to be a hormone that links obesity to diabetes. It was originally named for its resistance to insulin. Resistin serum levels were increased in obesity and resistin gene expression was induced during adipocyte differentiation (Fig. 1).
Although the first report proposed resistin serum levels to be increased in the obese state, a number of later publications have demonstrated decreased resistin gene expression in obesity. The way resistin was measured and the differences between serum concentrations and mRNA and protein levels probably contribute to the inconsistency observed in these studies. However, this does not necessarily rule out the possibility that resistin could still play a role in metabolic disorders. Some recent genetic studies have demonstrated an association between resistin and insulin resistance and obesity.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147
(i) Inhibitors of energy (food) intake (or appetite suppressants) reduce hunger perception, increase the feeling of fullness, and reduce food intake by acting on brain mechanisms. As a result, these drugs facilitate compliance with caloric restriction.
(ii) Inhibitors of fat absorption reduce energy intake through a peripheral, gastrointestinal mechanism of action and do not alter brain chemistry.
(iii) Enhancersof energy expenditure act through peripheral mechanisms to increase thermogenesis without requiring planned increases in physical activity.
(iv) Stimulators of fat mobilization act peripherally to reduce fat mass or decrease triglyceride synthesis or both without requiring planned increases in physical activity or decreases in food intake.
MSI-1436 appears to act differently than any other appetite suppressant. The compound may interact with calmodulin, a calcium sensing protein, to alter calcium signaling within certain cells of the brain. Squalamine, now in Phase 2 cancer trials (July 2000), is the first aminosterol discovered in the dogfish shark and works by sequestering calmodulin within the cell.
MSI-1436 may interact with calmodulin, a calcium sensing protein, to alter calcium signalling within certain cells of the brain.
New lipase inhibitor completes phase 1 trial.Alizyme plc announced on July 7 2000 that it successfully completed a Phase 1a clinical trial of its obesity drug ATL-962. ATL-962 is a lipase inhibitor that works similarly to the drug Xenical. ATL-962 is the only other lipase inhibitor being developed besides Hoffmann-LaRoche's Xenical. In pre-clinical studies the drug had similar efficacy to the Roche drug, and no toxicity was observed.