Molecular obesity

The prevalence of lipophilicity in these rules indicates how important it is to pay particular attention to this property. The term molecular obesity was introduced as a way to anthropomorphize the impact and danger of too much lipophilicity in compounds in development by analogy to the dangers of medical obesity [12]. The causative reasons why there is a tendency to allow lipophilicity to increase were also analyzed in this paper and Table 1.2 lists a number of the more obvious ones. 

Hann, M.M. (2011) Molecular obesity, potency and other addictions in drug discovery. Medicinal Chemistry Communications, 2, 349-355. 

Thus the ease of synthesis can be added to the search for potency and bioavailability as another factor underlying the observed propensity to pursue molecularly obese compounds. Based on ours and others experience, it seems that the ease of synthesis could be an even stronger driver than design. The current practices in organic chemistry make the design space seriously limited. (Hann and Keserii, p. 361). ... 

NIDDM is a much more common disease than IDDM, accounting for about 85—90% of all cases of diabetes meUitus. Whereas NIDDM may be present at any age, the incidence increases dramatically with advanced age over 10% of the population reaching 70 years of age has NIDDM. Patients with NIDDM do not require insulin treatment to maintain life or prevent the spontaneous occurrence of diabetic ketoacidosis. Therefore, NIDDM is frequendy asymptomatic and unrecognized, and diagnosis requires screening for elevations in blood or urinary sugar. Most forms of NIDDM are associated with a family history of the disease, and NIDDM is commonly associated with and exacerbated by obesity. The causes of NIDDM are not well understood and there may be many molecular defects which lead to NIDDM. 

A major adipokine, molecular weight 28,000 Da (monomeric form), that is secreted only from adipocytes. It exists at high levels in the plasma and has a number of fimctions, including an important role in insulin sensitivity, inflammation (anti-anti-inflammato-ry action) and atherogenesis. Unlike most adipokines, the plasma levels fall in obesity. 

Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., and O RahiUy, S. (2003) Mutations in the human melanocortin-4 receptor gene associated with severe famUial obesity disrupts receptor function through multiple molecular mechanisms. Hum. Mol. Genet. 12, 561-574. 

The leptin story has been augmented by a second mouse genetic defect leading to obesity. These mice are known as db/db they are very similar to ob/ob mice. However, these mice have normal levels of leptin. Scientists at Millennium Pharmaceuticals identified the molecular defect in db/db mice. They lack the normal leptin receptor. Therefore, we have both sides of the coin ob/ob mice cannot make leptin, eat too much, and are therefore obese db/db mice make leptin, cannot respond to it for lack of the leptin receptor, eat too much, and are obese. Administration of leptin to ob/ob mice normalizes their body weight but administration of leptin to db/db mice has... 

Although the exact molecular basis for the insulin resistance is not known, there are strong associations with obesity and a sedentary lifestyle. 

The metabolic abnormalities of obesity reflect molecular signals originating from the increased mass of adipocytes. The predominant effects of obesity include dyslipidemias, glucose intolerance, and insulin resistance, expressed primarily in the liver, muscle, and adipose tissue. 

Kadowaki T, Hara K, Yamauchi T, Terauchi Y, Tobe K, Nagai R. Molecular mechanism of insulin resistance and obesity. Exp Biol Med 2003 228 1111-1117. 

The discovery and cloning of the obesity gene (ob) in 1994 (Zhang et al. 1994) has led to an explosion of studies aimed at unraveling the molecular and cellular basis... 

Recent advances in molecular and cell biology have shown that adipose tissue not only stores excess energy in the form of fat, but also secretes physiologically active substances called adipocytokines (Matsuzawa et al., 1999). In obesity, adipocytes (cells of adipose tissues) are increased and enlarged, and they secrete excessive amounts of inflammatory adipocytokines, such as tumor necrosis factor-alpha (Hotamisligil et al., 1993) and monocyte chemoattractant protein-1 (Sartipy and Loskutoff, 2003). This induces type-2 diabetes, such as... 

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