Transcript Uncoupling proteins - Widener University

ob/ob mouse
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.
Leptin
Science 1996 December 6; 274: 1704-1707.
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).
Science 1996 December 6; 274: 1704-1707.
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.
Science 1996 December 6; 274: 1704-1707.
(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-cmdiameter 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.
Agouti Related
Proteins
Agouti mouse
http://www.bioscience.org/news/scientis/leptin1.htm
Ghrelin
DIABETES, VOL. 50, AUGUST
2001 Cummings et. al
http://endo.endojournals.org/cgi/reprint/142/10/4163.pdf
Candidate signaling molecules involved in energy
homeostasis
Catabolic
CRH*
*MSH
CCK
Bombesin
Somatostatin
Thyrotropin-releasing
hormone
Anabolic
NPY*
AGRP*
MCH
orexins A and B (=hypocretins 1 and 2)
galanin
b-endorphin
Calcitonin-gene–
related peptide
Neurotensin
Glucagon-like
peptide–1
dynorphin
norepinephrine
growth hormone–
releasing hormone
Serotonin
* These molecules are particularly important in the regulation of adiposity.
The role of satiety signals in
regulation of food intake
Integration of adiposity signals and
satiety signals
Long term regulation of body weight
Uncoupling
Proteins
Uncoupling proteins
UNCOUPLING PROTEINS
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
www.nature.com/tpj
The pharmacogenomics journal (2202) 2 :4-7 Ravussin, E.
www.nature.com/tpj
The pharmacogenomics journal (2202) 2 :4-7 Ravussin, E.
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).
Conclusions
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.
www.eje.org
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147
There are four general classes of antiobesity drugs.
(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.
Magainin Pharmaceuticals MSI-1436, a novel
drug.
http://www.obesity-news.com/omr08-00.htm#ucp3
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.
http://www.obesity-news.com/omr08-00.htm#ucp3
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 ATL962. 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.
MSI-1436 may interact with calmodulin, a calcium
sensing protein, to alter calcium signalling within
certain cells of the brain.