The Human Adipose Organ

As in small mammals, the adult human adipose organ is made up of subcutaneous as well as visceral depots. In normal adult individuals it accounts for about 9-18% of body weight in men and 14-28% in women. Most of the organ is located subcutaneously; its distribution is sex-dependent, the mammary and gluteo-femoral subcutaneous depots being more developed in women.

The visceral depots are very similar to those described in small mammals. In overweight or obese individuals, the abdominal visceral depots tend to grow in men and in post-menopausal women. This type of fat accumulation is dangerous for its association with the diseases secondary to overweight and obesity (diabetes, hypertension, myocardial infarct).

There are no histological differences between human and murine adipocytes, except for the larger size of the former. The maximum diameter measured in obese mice is ca. 140 ^m (about 1.30 ^g/cell in the epididymal depot), whereas in the subcutaneous depot of massively obese individuals the maximum diameter we measured is ca. 160 ^m (about 1.95 ^g/cell),a difference of 30-40%.

All the major molecules produced by murine fat cells (e.g. leptin, adiponectin, TNF-a, angiotensinogen, PAI 1, resistin, adipsin) are also produced by human adipocytes.

Human adipose tissue development entails a long phase of preadipocyte proliferation, which is complete at around 20 years of age. This is similar to rats and mice, where this phase is achieved by the second month of postnatal life [86].

Also in our species, regulation of the amount of fat tissue depends on the energy balance. If there is a positive balance, adult individuals exhibit an increase in adipocyte size, which, upon attainment of a critical size, will induce the development of new fat cells (see also 'Vessels and Nerves').

Indeed, the number of adipocytes, total fat mass and proportion of body fat correlate with age in both sexes, whereas adipocyte size does not appear to correlate with age, but with the amount of fat mass and its proportion of body weight in both sexes [87].

In massively obese individuals, the fat mass may quadruple to 60-70% of body weight [88,89]. Recent works reporting a massive presence of macrophages in the adipose tissue of obese subjects hypothesise that many cytokines produced by adipose tissue and responsible for most of the adverse symptoms of obesity are in fact histiocyt-ic in origin. The cause of this macrophage infiltration is unclear, but seems to be related to adipocyte size [90].

A negative energy balance induces a reduction in both fat mass and adipocyte size. The latter fact is important, because it results in improved cellular insulin sensitivity. Completely delipidised cells may be seen in the adipose tissue of individuals with a negative energy balance. Their morphology is very similar to that of the slimmed-down rat and mouse cells described above. In a TEM study of subcutaneous fat tissue from obese individuals administered a very low-calorie diet for 5 days, we detected severely slimmed-down adipocytes very similar to those observed in acutely fasted rats and mice. Interestingly, slimmed-down cells were side by side with unilocular adipocytes ostensibly not affected by the slimming process. The fate of completely slimmed-down cells is still unclear, and the hypothesis that they may undergo apoptosis is so far unsubstantiated.

Not all fat depots respond identically to a negative energy balance. Indeed, the gluteo-femoral subcutaneous tissue of adult pre-menopausal women is known to be much more resistant to the slimming process than abdominal subcutaneous fat, whereas both depots behave similarly in post-menopausal subjects. This seems to be due to a combination of increased lipoproteinlipase activity and reduced lipolytic activity in the former area.

The reduced lipolytic activity appears to stem from a relative preponderance of the antilipolytic activity of a2-ARs over that of lipolytic p-ARs [91]. In general, a2-ARs are more represented in human than murine adipose tissue. Transgenic mice with adipose tissue similar to human fat tissue have been obtained to mimic this situation in a murine model. These animals lack p3-ARs and express abundantly human a 2-AR (p 3-AR-deficient, human a2-expressing transgenic mice) [92]. In these animals obesity induced by a high-fat diet was exclusively of the hyperplastic type and the mice were not insulin-resistant. These data are in line with the important role of a2-AR in relation to the proliferative stimulus, and with the relationship between insulin sensitivity and adipocyte size.

Like the murine organ, the human adipose organ also contains BAT. Given its thermogenic function, animals with a small body volume and a larger relative body surface clearly have greater thermogenic requirements; the greater heat dissipation occurring in these compared with larger animals (which have a smaller volume/surface ratio) results in greater heat dispersion; hence, also the smaller proportion of human vs murine BAT. For the same reason, human newborns exhibit a greater amount of BAT than adults. In the human newborn's adipose organ, BAT occupies the same sites as in the murine organ. In the adipose organ of adult humans, several studies have detected small amounts of BAT with the same morphological and functional characteristics as murine BAT [93]. An increase in BAT in cold-exposed human subjects has also been reported [94]. Considerable amounts of BAT, especially perirenal, have often been described in patients with pheochromocy-toma (a tumour made up of endocrine cells secreting large amounts of adrenaline and noradrena-line) [95,96].

It has recently been demonstrated that human preadipocytes from different depots stimulated in vitro with thiazolidinediones (drugs that act by stimulating the PPARy transcription factor, which seems to have a large role in adipocyte differentiation) express UCP1 [97]. This suggests that human brown adipocyte development may be induced by drug treatment.

UCP1mRNA has been detected in the abdominal visceral depots of both lean and obese patients, though in significantly smaller amounts in the latter [98]. It is interesting to note that after dieting and consequent weight loss, UCP1mRNA levels remained lower than in lean subjects, suggesting a lesser genetic predisposition to energy dispersion in obese individuals [99]. This is in line with the observation that combined mutations of UCP1 and p3-AR induce additive effects on weight gain in human obesity [100].

Two recent papers stress the importance of the concept of the adipose organ in humans. In the first, in agreement with the experimental finding that transgenic mice lacking insulin receptor at the sole level of BAT are hyperglycaemic, a reduced 'brown' phenotype in human subcutaneous adipose tissue has been shown to predispose to diabetes [101]. In the second, in vitro transfection of PPARy co-factor 1 (PGC1, see above) induced the transformation of human white adipocytes into fat cells capable of expressing UCP1, the molecular marker of brown adipocytes [75].



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