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MEDICAL BIOLOGY: BILE ACIDS, THYROID HORMONE, AND OBESITY

The following points are made by J.D. Baxter and P. Webb (Nature 2006 439:402):

1) Obesity is pandemic in the Western world and is becoming a problem in other countries[1]. Stroke, heart attack, diabetes, kidney failure, arthritis, and peripheral vascular disease are all consequences of this disorder. But the outlook is not all bleak. If obesity can be reduced, there should be enormous health benefits -- even a 5% decrease in body weight through diet and exercise cuts the risk of type 2 diabetes by more than 50%[2]. Nevertheless, efforts to address the problem by encouraging life-style modifications have met with limited success. So major efforts are under way to find other therapies. New work[3] reports a previously unappreciated role for bile acids in regulating fat that might also be exploited pharmacologically to tackle obesity.

2) Body-weight control is essentially a question of energy balance: if we eat more calories than we expend, we become fat[4]. Many therapies, therefore, aim to reduce food intake. Surgery has had impressive results, but carries substantial risks. Current pharmacological manipulation of the pathways that regulate appetite or block dietary fat absorption have limited utility. High-fat, fast-food diets can override delicate regulatory networks established by appetite-regulating hormones, and it has been difficult to develop drugs that reduce food intake in the face of powerful environmental influences. Moreover, drugs that block fat absorption have limited efficacy.

3) Are there other approaches to combat obesity? Endocrinologists have long known that hormones can alter the body's fat content. And although they cannot override the laws of thermodynamics, hormones do alter the energy-balance equation by increasing metabolic rate. An illustration of this principle is seen in disorders involving excess thyroid hormone, where stimulation of metabolic rate and decrease in body fat can occur even with increased dietary intake. Thyroid hormone itself cannot be used to treat obesity because of deleterious side effects that can include increased heart rate, atrial arrhythmias and breakdown of muscle and bone. But manipulating this pathway may be useful, and selective analogues of thyroid hormone are already showing promise in reducing body fat in animals[5].

4) Watanabe et al[3] report that bile acids have a role in regulating thyroid hormone signalling and energy homeostasis. Although the classical role for bile acids is to enhance fat absorption in the intestine, they also regulate the metabolism of fat by acting as signalling molecules through pathways involving the cell-surface receptor TGR5 and nuclear receptors such as FXR. Watanabe et al[3] show that bile acids, which include cholic acid, stimulate production of active thyroid hormone in fat cells


References (abridged):

1. Hedley, A. A. et al. J. Am. Med. Assoc. 291, 2847 2850 (2004)

2. Gaede, P. et al. N. Engl. J. Med. 348, 383 393 (2003)

3. Watanabe, M. et al. Nature 439, 484 489 (2006)

4. Spiegelman, B. M. & Flier, J. S. Cell 104, 531 544 (2001)

5. Baxter, J. D. et al. Trends Endocrinol. Metab. 15, 154 157 (2004)

Nature http://www.nature.com/nature

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Related Material:

OBESITY AND THE RISK OF HEART FAILURE

The following points are made by S. Kenchaiah et al (New Engl. J. Med. 2002 347:305):

1) Heart failure is a major health problem that is increasing in scope.(1) Despite recent therapeutic advances, morbidity and mortality after the onset of heart failure remain substantial.(1) Consequently, prevention of heart failure through identification and management of risk factors and preclinical phases of the disease is a priority.(2) In this context, several studies have evaluated body-mass index (the weight in kilograms divided by the square of the height in meters) as a risk factor for left ventricular remodeling and overt heart failure. In these investigations, obesity has been consistently associated with left ventricular hypertrophy and dilatation,(3-5) which are known precursors of heart failure. Whereas extreme obesity has been associated with heart failure, data are limited regarding the influence of overweight and lesser degrees of obesity on the risk of heart failure. Accordingly, the authors investigated the relation of body-mass index with the risk of heart failure in a community-based sample.

2) The authors investigated the relation between the body-mass index and the incidence of heart failure among 5881 participants in the Framingham Heart Study (mean age, 55 years; 54 percent women). During follow-up (mean, 14 years), heart failure developed in 496 subjects (258 women and 238 men). After adjustment for established risk factors, there was an increase in the risk of heart failure of 5 percent for men and 7 percent for women for each increment of 1 in body-mass index. As compared with subjects with a normal body-mass index, obese subjects had a doubling of the risk of heart failure. For women, the hazard ratio was 2.12 (95 percent confidence interval, 1.51 to 2.97); for men, the hazard ratio was 1.90 (95 percent confidence interval, 1.30 to 2.79).

3) The authors conclude that in their large, community-based sample, increased body-mass index was associated with an increased risk of heart failure. The authors suggest that given the high prevalence of obesity in the US, strategies to promote optimal body weight may reduce the population burden of heart failure.

References (abridged):

1. American Heart Association. 2002 Heart and stroke statistical update. Dallas: American Heart Association, 2001

2. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101-2113

3. Messerli FH, Sundgaard-Riise K, Reisin ED, et al. Dimorphic cardiac adaptation to obesity and arterial hypertension. Ann Intern Med 1983;99:757-761

4. Hammond IW, Devereux RB, Alderman MH, Laragh JH. Relation of blood pressure and body build to left ventricular mass in normotensive and hypertensive employed adults. J Am Coll Cardiol 1988;12:996-1004

5. Lauer MS, Anderson KM, Kannel WB, Levy D. The impact of obesity on left ventricular mass and geometry: the Framingham Heart Study. JAMA 1991;266:231-236

New Engl. J. Med. http://www.nejm.org

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ON DIABETES, OBESITY, AND ADIPOCYTES

The following points are made by A.R. Shuldiner et al (New Engl. J. Med. 2001 345:1345):

1) Although 100 years ago type 2 diabetes mellitus was considered a rare disease, there has recently been an explosive increase in its incidence: currently, approximately 16 million Americans have type 2 diabetes, and at least an equal number have impaired glucose tolerance. Insulin resistance and hyperinsulinemia are characteristic of both type 2 diabetes and impaired glucose tolerance. These metabolic derangements, combined with the hypertension and abnormal blood lipids that are common in type 2 diabetes and impaired glucose tolerance, markedly increase the risk of cardiovascular, peripheral vascular, and cerebrovascular disease.

2) Why has the incidence of type 2 diabetes increased so rapidly? Considerable epidemiologic evidence points to excess caloric intake and physical inactivity as the major reasons. A chronic imbalance between energy expenditure and energy intake causes obesity, which is one of the most potent risk factors for insulin resistance and type 2 diabetes. These epidemiologic observations underscore the importance of the relation of adipose tissue to insulin resistance and glucose intolerance.

3) Recent studies have transformed our thinking about the adipocyte. This cell type is no longer regarded as a passive depot for storing excess energy in the form of triglycerides, but as a cell that actively regulates the pathways responsible for energy balance and whose activity is controlled by a complex network of hormonal and neuronal signals. Indeed, the adipocyte secretes chemical messengers that include leptin, tumor necrosis factor alpha, angiotensinogen, and adiponectin. The most recently discovered adipocyte-secreted hormone is resistin, which may be an important link between increased fat mass and insulin resistance.

New Engl. J. Med. http://www.nejm.org

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