Functional Anatomy of White Adipose Tissue

Important discoveries in the 1990s rekindled the interest in white adipose tissue. In December 1994, the team of Friedman at New York Rockefeller

University discovered the gene of obesity [8]; their subjects were mice, which in the 1950s had developed a spontaneous mutation resulting in hyper-phagia, infertility and reduced activity of the sympathetic nervous system, and consequently in early, massive obesity (ob/ob mice) [9].

The alteration - detected on chromosome 6 -consisted of a C to T point mutation at codon 105, turning it into a stop codon and interrupting the synthesis of a 167 amino acid secretion protein, which was named leptin from the Greek leptos (thin) [8]. The mouse gene appears to be expressed solely in WAT and is 84% homologous to the human gene.

Within a few months, three groups demonstrated independently that leptin administration to obese mice corrected in a few weeks all the defects related to its absence, and that treated mice were then no longer distinguishable from lean controls [10-12]. The leptin receptor was discovered in 1995 [13]. Demonstration of at least five alternatively spliced forms [14], and reports that the functional form (i.e. the one activating intracellular signalling) appears to be prevalently expressed at the hypothalamic level and is mutated in mice phenotypically very similar to ob/ob mice (except for a proneness to develop diabetes, hence called db/db) [14,15],came the following year.

These findings lent support to the hypothesis -advanced by Coleman in the 1970s based on parabiosis experiments [16] - that a circulating lipo-static factor must be implicated in maintaining body fat constant. By making the blood of lean and ob/ob mice circulate in parabiosis, Coleman noted that obese mice lost weight, benefiting from the lipostatic factor present in the bloodstream of lean mice. The same did not apply to db/db mice, since whereas ob/ob mice do not produce leptin, db/db ones do not produce its functional receptor.

The researchers' enthusiasm was dampened by a paper in which Maffei [17] reported in a large sample of patients an unexpected, close correlation between BMI (the body mass index obtained by calculating the ratio of weight in kg to the square of height in metres) and leptinaemia; as this entails that obese subjects have high values of leptinaemia and are thus prone to leptin resistance, they would be unaffected by the leptin treatment beneficial to ob/ob mice. Until now, rare cases of human genetic leptin deficiency have been discovered and successfully treated with leptin [18].

Flyer, noting that its administration restored plasma levels of thyroid, adrenal and gonadal hormones in fasting mice, hypothesised a prominent role for leptin in controlling the endocrine secretion in relation to food intake [19]. Accordingly, leptin functional receptors were identified in several peripheral organs [20], considerably broadening its role.

Further sites of leptin production were identified in placenta, mammary gland, stomach and salivary glands, further supporting the notion of a wider functional action of this protein (in vasculo-genesis, immune defence, food absorption) (see [21] for a review).

These reports revolutionised the concept of WAT, which finally came to be recognised as a real endocrine tissue capable of affecting the feeding behaviour of mammals.

Over time, other molecules were reported to be WAT secretion products (adipokines), and the relationship between their excessive secretion and the severe complications of obesity became increasingly apparent. Especially interesting was the correlation between secretion of tumour necrosis factor (TNF)-a, resistin and adiponectin and diabetes; between angiotensinogen and min-eralocorticoid-releasing factors and arterial hypertension [21]; and between plasminogen activator inhibitor (PAI 1) and coagulation problems [22]. These data contributed to clarify the molecular mechanism underpinning the early clinical observation that androgenic obesity (i.e. central adiposity with a greater accumulation of visceral fat) carries more dangerous complications than gynoid obesity (peripheral adiposity with a greater accumulation of subcutaneous fat), because of the inhomogeneous secretion of adipokines across depots. An especially close relationship was described for adiponectin and diabetes.

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