Androgens play an important role in regulating the central obesity that is a strong risk factor for cardiovascular disease and insulin resistance. This study confirms that androgen receptors are present in subcultured human preadipocytes, with androgen receptor gene expression and saturable specific dihydrotestosterone binding, dissociation constant 1.02 - 2.56 nM and maximal binding capacity 30.8 - 55.7 fmol/mg protein. There was an intrinsic regional difference in androgen receptor complement, with more androgen receptors in visceral than in subcutaneous preadipocytes. Dihydrotestosterone was metabolised by human preadipocytes, with more androstanediol produced by subcutaneous than visceral preadipocytes. While dihydrotestosterone metabolism was insufficient to explain the regional variation in androgen binding, both of these differences would reduce the androgen responsiveness of the subcutaneous preadipocytes compared with visceral preadipocytes. There were no gender differences in androgen binding or metabolism. While the direct effects of androgens on human PAs remain uncertain, these regional differences suggest that AR-mediated regulation of certain PA functions influences adipose tissue distribution.

The hormone-substrate milieu has been investigated in male fasted lean (C57BL/6-+/+) mice and mutant obese mice of the same strain (C57BL/6-obob). The lean mouse, in winter, mobilized insufficient fat (due to inadequate stores) to permit survival beyong 3 days and was unable to achieve any degree of conservation of vital protein stores. By contrast, in summer, the same animals survived 7 days and showed evidence of greater and more sustained fat mobilization and ketosis and the ability to conserve protein. The insulin, glucagon, and insulin/glucagon molar ratios changed in both groups in a direction consistent with conversion to a catabolic state, and hence were probably largely responsible for the mobilization of substrates and stimulation of gluconeogenesis and ketogenesis. The seasonal difference in response is unexplained. The obob mice, generally employed as a model for obesity, hyperglycemia, and hyperinsulinemia showed these features but also adapted to fasting in a fashion permitting prolonged survival during this state. In a fashion analogous to that known to occur in man, these animals developed fall in glycemia, rise in circulating fat-derived substrates, and marked protein conservation. Profound fall in insulinemia was associated with a fall in glucagonemia, the latter from normal levels. Thus the initial markedly "anabolic" insulin/glucagon molar ratio diminished, but nevertheless remained higher than at any time in the lean mice. Pancreatic contents of insulin showed markedly different changes with fasting in obob compared with lean mice. The ability of the obese mouse to adapt to prolonged fasting in a fashion largely analogous to that of man renders it a useful model for the study of metabolism in this state, with the potential of applicability of findings to man.

Glucocorticoid excess causes visceral obesity and its accompanying insulin resistance, dyslipidemia and hypertension.

Diabetic mice of the C57BL/6J obob and C57BL/Ks dbdb strains show a reduction in pancreatic somatostatin concentration accompanied in the obob strain by a striking decrease in the number of somatostatin-containing cells in the islets. Somatostatin concentration is also decreased in the stomach but increased in the hypothalamus. These findings suggest different control mechanisms for somatostatin in the hypothalamus compared to the gut and pancreas and exclude a primary genetic abnormality of somatostatin cells in the mutants.

Streptozotocin (STZ) is believed to induce pancreatic cell death in mice by depleting the cell of NAD+NADH. The drug is known to cause a greater depletion of cell NAD+NADH in C57bl/6J mice than in Balb/c mice. To investigate the basis for this strain difference, we compared the effects of streptozotocin on poly(ADP-ribose)-polymerase (PARP) activation -the major site of NAD consumption, and on mitochondrial activity -the major site of NAD production.A significant strain difference was demonstrated in STZ-induced PARP activation (fmol NAD incorporated/min/ µg DNA ...: Balb/c control 2·28 0·14, Balb STZ 3·11 0·25; C57bl/6J control 2·57 0·29, C57bl/6J STZ 4·17 0·24). In comparison, no strain difference could be demonstrated in hydrogen-peroxide-induced PARP activation. No strain differences could be detected in the activity of STZ-treated islet mitochondria as measured by determining ATP production (pmol/ µg protein/h ...: Balb/c control 0·20 0·02, Balb/c STZ 0·15 0·02; C57bl/6J control 0·23 0·03, C57bl/6J STZ 0·15 0·02) or by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dye reduction (change in optical density/mg protein ...: Balb/c control 10·19 0·62, Balb/c STZ 6·01 1·17; C57bl/6J control 6·15 0·98, C57bl/6J STZ 5·81 0·96).The strain difference in STZ-induced NAD depletion appears to be due to a difference in NAD consumption and not a difference in a mitochondrial process involved in replacing decreasing NAD concentrations. It is unlikely that a strain difference in the enzymic activity of PARP is responsible for strain differences in the effects of STZ, as no strain differences in hydrogen-peroxide-induced PARP activation could be detected. Thus the greater PARP activation, NAD depletion and cell death observed in C57bl/6J islets may be due to greater levels of DNA damage or differences in the DNA excision repair processes.