Obesity, hypertension, and insulin resistance.

1 T his article summarizes material presented at the meeting of the American Society of Hypertension (ASH) in New York, New York, May, 2002, as well as presentations at the American Diabetes Association (ADA) Annual Meeting in San Francisco, California, June, 2002. At a symposium addressing the relationships between obesity, hypertension, and cardiovascular disease at the ASH, Roger Unger (Dallas, TX) discussed lipotoxicity and the metabolic syndrome. He pointed out that over that past 50 years there has been a great change in the food environment, so that the “mechanism for preloading calories, storing them for when a famine occurred,” has led to “hypertrophy and hyperplasia of those adipocytes [. . . ]. Famines were eliminated and replaced by a never-ending stream of highquantity, high-fat, high-carbohydrate foods at the same time that physical exertion dropped to an all-time low.” This has led to a progressive increase in obesity, particularly over the past two decades. “As long as the excess fat remains in the adipocyte,” he stated, “health is not deleteriously affected,” but an “increase in ectopic deposition of lipids” causes the insulin-resistant state, with insulin resistance per se characterized by Unger as “not the proximal cause of the syndrome.” Unger examined monogenic disorders of lack of leptin action to understand “the mechanism of the disorder.” These syndromes, which lead to components of the metabolic syndrome, suggest that leptin resistance or deficiency may be a more central cause than insulin resistance. The normal actions of leptin can be seen in animal models of obesity, with overfeeding leading to hyperleptinemia, which may cause fat to deposit primarily in the adipocyte. Normal islets, as an example, “fill up with triglycerides” when incubated with fatty acids, but this can be prevented by administration of leptin. When leptin action is insufficient, as seen in the fatty/fatty (fa/fa) rat with loss-offunction mutation of the leptin receptor or the leptin-deficient ob/ob rat, there is a marked increase in tissue fat. fa/fa rats show both heart and muscle “loaded with triglyceride,” suggesting that “leptin increases tolerance for fat just as insulin increases tolerance for glucose.” Obesity in the fa/fa animal leads to an increase in cardiac output to maintain the needs of excess body tissue. Cardiac function deteriorates, with initial cardiac hypertrophy leading to a pattern resembling that seen in dilated cardiomyopathy. Increased cardiomyocyte apoptosis, as shown by DNA laddering, can be seen in this setting. Levels of the sphingomyelin derivative ceramide increase with obesity and may mediate these effects, and blockers of serine palmityl transferase (which condenses palmityl CoA with serine to form ceramide) can prevent this process. Ceramide precursors lead to more rapid ceramide synthesis and increase insulin resistance in these animal obesity models. In the islets, after diabetes has occurred in these models, extensive mitochondrial damage is seen in -cell remnants, a process prevented by troglitazone administration. High levels of fatty acids suppress anti-apoptotic processes, while a transgenic fa/fa model overexpressing leptin receptors in the islets is protected from this fat-induced apoptosis. Aspects of these processes appear to occur in human obesity. Tissue triglyceride may be synthesized from glucose as well as from circulating free fatty acids (FFAs), or may derive from VLDL triglyceride, suggesting multiple potential sources of lipotoxicity. Myocyte fat levels, measured using magnetic resonance scanning, show correlation with the degree of adiposity and obesity may be associated with increased myocardial fat in humans. Unger suggested that the condition of “fatty heart,” originally noted by William Harvey and subsequently studied by early cardiologists, should be more of a concern. Gerard Ailhaud (Nice, France) discussed the differing metabolic characteristics of visceral and subcutaneous (SC) fat. Adipose tissue plays a role in energy regulation and can be considered a secretory organ supplying energy needs during exercise via FFAs. “The problem is the management of levels” of FFAs. In vitro studies suggest that the smaller visceral adipocytes undergo more lipolysis, with more -adrenergic receptors leading to greater activity of hormone-sensitive lipase, while insulin has a stronger antilipolytic effect on the larger SC adipocytes, which have greater -2 adrenergic receptor levels. Thus, the -2 adrenergic response leads to accumulation of fat, but in a fashion of potential benefit in terms of sequestration of fatty acids in the adipocyte, with similarity to the effects of thiazolidinedione administration. Local production of cortisol may be greater in visceral fat, while tumor necrosis factor (TNF)and leptin are produced to a greater extent in SC fat. Exercise promotes mobilization of lipid from SC adipocyte tissue in nonobese individuals, but this process is decreased in obesity and can be restored by administration of the -2 adrenoreceptor antagonist phentolamine. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●