THE LATEST IN OBESITY RESEARCH AND WEIGHTLOSS DRUG DEVELOPMENT
Volume 5, Issue 4/5 April/May 2001
LOSE WEIGHT AND KEEP IT OFF?
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Obesity-news.com
THE LATEST IN OBESITY RESEARCH AND WEIGHTLOSS DRUG DEVELOPMENT
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Drug development.
A hormone that causes fat loss.
We all know people who eat mountains of food and get little exercise, but never seem to gain weight. Well, it appears that those skinny folks may have a high level of a certain hormone, known as melanocyte-stimulating hormone (MSH), while
less blessed individuals exercise for hours a week and pass up dessert only to remain frankly, pudgy.
EXPERIMENTS
Leptin deficient (ob/ob) mice and controls were treated with leptin to test the effect of the hormone on circulating MSH levels.
Ob/ob mice and controls were treated with leptin, an MSH analog, both, or placebo to evaluate the effects on body weight and food intake.
Ob/ob mice and controls were injected with an MSH analog or placebo and then fasted to measure its effect on metabolic rate.
Ob/ob mice and controls were treated with an MSH analog or placebo to measure its effects on thermoregulation.
Ob/ob mice and controls were treated with an MSH analog or placebo to measure its effects on serum FFA levels.
Dr. Miles B. Brennan and colleagues at the Eleanor Roosevelt Institute in Denver, CO have found that MSH plays an important role in regulating body weight by altering lipid metabolism. In a series of experiments, MSH was found to regulate fat metabolism in the periphery by discouraging the storage of adipocytes and increasing metabolic rate. The results were published in the March 17 issue of the Proceedings of the National Academy of Sciences. In a university press release, investigators commented that MSH could be tested on humans as early as this year, research that may produce a pill, patch or nasal spray which could be used to trigger weight loss without any change in diet or exercise levels.
The central role of MSH in body weight regulation has long been understood. MSH secreted in response to hypothalamic leptin binds to the melanocortin-4 receptor (MC4-R) resulting in appetite suppression. But rodent experiments suggest that the role of MSH in body weight regulation is broader than the simple control of appetite. For example, animals lacking the MSH precursor, proopiomelanocortin (POMC), demonstrate lipid metabolism irregularities in addition to hyperphagia. However, when POMC knockouts are treated with an α-MSH analog they lose weight but do not reduce their food intake. This is an indication that MSH may be mobilizing peripheral fat stores. Both leptin deficient mice and humans also express unexplained irregularities in metabolism which may be explained by a peripheral role for MSH.
Results.
The study found that 1) leptin injection increased the levels of circulating MSH, and peripherally administered MSH analog 2) slowed weight gain through an increase in metabolism, 3) accelerated weight loss during a fast, 4) improved the impairment of thermal regulation, and 5) stimulated FFA levels in ob/ob mice.
Experiment 2: MSH increases metabolism. Whereas both leptin treatment and MSH analog treatment effectively slowed weight gain, the effect of MSH analog was greater on energy expenditure than intake. Compared with the food intake of untreated ob/ob controls, leptin deficient mice receiving MSH analog ate only 0.327 grams less, whereas leptin treatment decreased daily food intake by 1.17 grams. These results indicate a reversal of the decreased metabolic rate of ob/ob mice by the MSH analog.
Experiment 3: MSH produces accelerated with loss during a fast. During a fast both control and ob/ob mice lost significantly more weight with MSH analog treatment than with placebo.
Experiment 4: MSH improves thermal regulation. Ob/ob mice treated with MSH analog maintained their core temperature during a cold challenge much better than placebo treated ob/ob mutants. As the mice had no opportunity to eat between the injection of the MSH analog and the cold exposure, food intake could not be responsible for the alteration in thermal regulation. This indicates that the improvement was attained through an increase in mobilization of energy stores.
Food
Weight Gain
Control
548g
57.2g
MSH
511g
38.8g
Leptin
431g
27.8g
MSH + leptin
433g
28.8g
Experiment 5: MSH stimulates FFAs. Control mice increased FFAs by 11.4 percent and ob/ob mice by 18 percent with MSH analog treatment. The finding that MSH analog stimulates serum FFA levels suggests that the altered metabolism in ob/ob mice and lipid metabolism are related.
Conclusions.
Researchers propose that MSH contributes to a leptin-induced decrease in appetite and increase in metabolic rate, which are complementary responses to sufficient fat stores. The central effect of MSH on appetite is mediated through MC4-R whereas the increased metabolic rate is mediated by peripheral cells, especially adipocytes expressing MC-Rs.
Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway. Forbes S, et al. (medline) Proc Natl Acad Sci U S A 2001 Mar 27;98(7):4233-4237.
Nutrition studies.
Dietary fat and the weight-reduced woman.
A study, conducted at the Mike Rosenbloom Laboratory for Cardiovascular Research and the School of Dietetics and Human Nutrition at McGill University, has found that postobese women may be more prone to weight gain because of the way that they metabolize fat. In an experiment conducted on 8 weight-reduced women and 8 controls, researchers found that there was an increase in the amount of fat stored in women who were once obese caused by enhanced fatty acid trapping in peripheral tissues. These results raise the possibility that the abnormality is part of the pathogeneisis of obesity.
BASELINE CHARACTERISTICS OF SUBJECTS
Control (n=8)
Postobese (n=8)
Age
37.5 ± 1.9
40.3 ± 2.1
Weight (kg)
63.5 ± 2.2
63.6 ± 2.8
Height (cm)
166.5 ± 1.6
163.7 ± 1.5
BMI
22.8 ± 0.7
23.7 ± 0.9
BSA
1.67 ± 0.03
1.78 ± 0.04
Waist-to-hip ratio
0.74 ± 0.01
0.78 ± 0.02
Percent body fat
32.6 ± 1.7
30.9 ± 2.6
FFM (kg)
42.5 ± 1.2
43.5 ± 1.2
Fat mass (kg)
20.8 ± 1.6
20.0 ± 2.4
TG (mM)
0.80 ± 0.11
0.78 ± 0.08
NEFA (mM)
0.42 ± 0.08
0.38 ± 0.05
Cholesterol (mM)
4.15 ± 0.19
3.78 ± 0.20
HDL (mM)
1.51 ± 0.12
1.45 ± 0.13
LDL (mM)
2.29 ± 0.21
2.00 ± 0.14
apoB (mg/dl)
71.4 ± 5.1
69.0 ± 5.8
Glucose (mM)
4.33 ± 0.15
4.38 ± 0.21
Insulin (pM)
117.5 ± 8.3
126.9 ± 5.9
ASP (nM)
23.4 ± 4.9
21.3 ± 3.4
Leptin (ng/ml)
9.5 ± 1.4
5.1 ± 0.8
subjects. Eight postobese women and 8 normal weight controls. The postobese subjects had been morbidly obese (BMI > 40) and underwent gastric bypass surgery 2-3 years before the study. Both subjects and controls met the following inclusion criteria:
Thirty to 50 years of age with regular menstruation,
BMI between 20 and 27,
Normal lipids, insulin and glucose,
No history of cardiovascular disease, diabetes, hypertension, gastrointestinal, respiratory or hormonal disorders,
Not taking medications that affect lipid metabolism within 6 months of the study,
Weight stable for a least 6 months.
All subjects had body fat measured by electric conductivity, and were between 2 and 7 days after menstruation.
Methods. Subjects came in at 8 a.m. after an overnight fast. Baseline weight, height, BMI, body surface area (BSA), body fat, resting energy expenditure (REE) and substrate oxidation rate were measured. Fasting blood and breath samples were collected. All subjects were then given a high fat meal equal to approximately 60 percent of their daily caloric requirement. They were instructed to eat the meal within a 20 minute time period and lie down after food consumption.
Results.
Baseline characteristics of subjects are contained in the table. None of the fasting plasma values were significantly different between the two groups except for fasting leptin, which was markedly reduced in the postobese group. The high fat meal was well tolerated, and neither group reported feelings of dizziness, flushing or sweating, symptoms associated with accelerated or delayed gastric emptying.
Increased fatty acid trapping in postobese subjects. There was a faster clearance of dietary TG and much less coleate entering the NEFA pool in the postobese group, both of which are indications of enhanced fatty acid trapping by peripheral tissues in the postobese women. Fatty acids can either be released into plasma as non esterified fatty acids (NEFA) or enter peripheral cells and be stored as fat. The two groups differed sharply with regard to the fate of the released dietary fatty acids, evidenced by the small amount of coleate released into the NEFA pool in post obese subjects compared to controls.
Gastric bypass was not considered a factor in these results, because the procedure does not produce significant fat malabsorption. Neither could the difference be accounted for by dumping syndrome, a condition that can occur early after surgery particularly after a high carbohydrate liquid intake. Finally, the postobese women had normal fecal fat content eliminating differences in fat absorption as an explanation for the findings.
Enhanced dietary fat clearance in postobese women. Faraj M, et al. (medline) J Lipid Res. 2001 Apr;42(4):571-80.
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