Transcript Uncoupling proteins - Widener University

Energy Balance--- What should we teach our
students?
Energy Balance--- What should the
textbooks teach our students?
Itzick Vatnick ---Widener University
URL: htpp://science.widener.edu/~vatnick
email [email protected]
HAPS 17th Annual
Conference
Energy Balance
Body weight
Negative Energy Balance
Body weight
Positive Energy Balance
Body weight
Energy in
home.wanadoo.nl/fox-1/ farside/eating.gif
Editorial comment:
No more Larson?
How do we measure
energy in foods?
kilocalorie (kcal):
eg. a half cup of peanut butter contains ~750 kcal; or
enough energy to heat 750 L of water by 1°C !!
SI unit is the kilojoule (kJ): kcal x 4.184
energy content of food measured by direct
calorimetry
complete combustion of known amount of food in a
sealed, insulated container measure increase in
temperature of surrounding water jacket known as
bomb calorimetry
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
Gross energy content of macronutrients, determined by
combustion
carbohydrate: 4.2 kcal per gram
fat: 9.4 kcal per gram (due to greater relative hydrogen
content)
protein: 5.6 kcal per gram
Actual (net) energy content of macronutrients (called Atwater
General Factors)
loss of H atoms as urea (ie. loss of protein energy)
coefficient of digestibility
usually > 90%, some variability
reduced by dietary fiber
generally NOT different between lean and obese
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
Macronutrient
Atwater General Factor
Carbohydrate
4 kcal per gram
Fat
9 kcal per gram
Protein
4 kcal per gram
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
Respiratory Exchange Ratio (RER)
VCO2 / VO2; reflects “blend” of fat/CHO oxidized
0.70, pure fat
1.00, pure carbohydrate
assume negligible contribution from protein (i.e. non-protein
RQ)
C6H12O6 + 6 O2
C16H32O2 + 23 O2
0.70)
6 CO2 + 6 H2O (RER = 6 CO2 / 6 O2 = 1.00)
16 CO2 + 16 H2O (RER = 16 CO2 / 23 O2 =
measured at lungs (i.e. whole body), but in theory, reflective of
Respiratory quotient (RQ; at level of mitochondrion)
influenced by non-steady state conditions (VCO2)
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
RER is a relatively sensitive scale i.e. differences of
0.02 units translate to substantial differences in energy
derived from each substrate
Example: exercise at ~ 75% VO2 max (3.0 L/min) for 60
min
If average RER = 0.80 (i.e. 2.4 / 3.0):
4.801 kcal/L O2 x 3.0 L/min x 60 min = 864 kcal
33.4 % kcal from CHO = 289 kcal
66.6 % kcal from fat = 575 kcal
If average RER = 0.82 (i.e. 2.46 / 3.0):
4.825 kcal/L O2 x 3.0 L/min x 60 min = 869 kcal
40.3 % kcal from CHO = 350 kcal
59.7 % kcal from fat = 519 kcal
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
Energy OUT
Total Daily Energy Expenditure
(TDEE)
RMR
TEF
TA
Total Daily Energy Expenditure (TDEE)
RMR
Resting/basal Metabolic Rate (60-75%) “essential”
(maintenance of ionic gradients, substrate cycles, etc.)
ion homeostasis, 40-60% (20-30% from Na/K ATPase
alone)
protein turnover, 25%
mitochondrial uncoupling, 20-30%
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
main contributing tissues: skeletal muscle and liver (despite
its small mass!)
Tissue Contribution
(%)
Mass (%)
Liver
26
3
Muscle
26
40
Brain
18
2
Heart
9
<1
Kidneys
7
<1
other
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
14
Total Daily Energy Expenditure (TDEE)
TEF-- Thermic Effect of Food
Also known as specific dynamic action (SDA) and heat
increment of feeding (HIF)
obligatory (digesting, absorbing, assimilating)
facultative (stimulatory effect on metabolism, SNS)
mixed meal elevates RMR by 25-50%, but only lasts ~2-4
hours
splanchnic (gut, liver, pancreas) VO2 increases 50%
muscle (leg) VO2 increases 30%
thermic effect reduced in obese individuals
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
also, note that the metabolic consequences of
individual macronutrients differ considerably
amino acids; 50% increase in splanchnic VO2
glucose; 8-13% increase in muscle VO2
fat; little change in VO2
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
Total Daily Energy Expenditure (TDEE)
PA
Physical Activity (15-30%)
http://www.uoguelph.ca/hb+ns/NUTR4210/BasicNotes.pdf
Energy Balance
Body weight
What controls energy intake?
The glucostatic theory
The liposatic theory
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
The evidence so far…
A few years later ….
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
The evidence so far…
A simplified model of the action
of ghrelin and leptin on feedingregulatory circuitry. Leptin acts as
part of a feedback loop to maintain
constant stores of fat5. Leptin is
released from adipocytes as a
function of the amount of fat, and
reduces food intake by acting on two
hypothalamic pathways. It stimulates
an anorexigenic pathway and inhibits
anorexigenic pathway; both of them
originate in the arcuate nucleus of
the hypothalamus andproject to the
paraventricular nucleus and the lateral
hypothalamic area
Ghrelin is released from the
stomach. The effect of ghrelin in the
hypothalamus is opposite to that of
leptin; in other words, ghrelin acts as
an orexigenic molecule. In addition,
ghrelin stimulates both energy gain
and the secretion of growth hormone
(GH) by acting directly on the
anteriorpituitary. So, the action of
ghrelin constitutes an integrated
means to produce an anabolic state
and growth. Fasting decreases leptin
and increases ghrelin production,
leading to the activation of the
orexigenic pathway. This response
might be important for adaptation to
fasting. Although ghrelin is also
produced by hypothalamic cells, it
remains to be seen whether this
source has a similar action to ghrelin
produced by the stomach. GHRH,
growth-hormone-releasing hormone.
Nature Reviews Neuroscience 2; 551-560 (2001);
What controls energy expenditure?
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 tissuedistribution, 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
A new view on…
www.deltagen.com/.../ adipose_tissue_white_40x.jpg
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.