Adipose Tissue Of Obese Humans Research Articles

Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

Enhanced glycerol 3-phosphate dehydrogenase activity in adipose tissue of obese humans.

The primary purpose of this investigation was to determine whether adipose tissue glycerol 3-phosphate dehydrogenase activity is associated with human obesity. The data presented in this paper indicate that the glycerol 3-phosphate dehydrogenase activity in adipose tissue from morbidly obese subjects is approximately 2-fold higher than from lean individuals. Moreover, positive correlation between adipose tissue glycerol 3-phosphate dehydrogenase activity and body mass index (BMI) (r = 0.5; p < 0.01) was found. In contrast, the adipose tissue fatty acid synthase (FAS) and ATP-citrate lyase (ACL) activities in morbidly obese patients are significantly lower than in lean subjects. Furthermore, negative correlation between adipose tissue FAS activity and BMI (r = -0.3; p < 0.05) as well as between ACL activity and BMI (r = -0.3; p < 0.05) was found. These data indicate that elevated glycerol 3-phosphate dehydrogenase might contribute to the increase of triacylglycerol (TAG) synthesis in obese subjects, however, fatty acids necessary for glycerol 3-phosphate esterification must be derived (because of lower FAS and ACL activities) mainly from TAG in circulating lipoproteins formed in liver (VLDL), and/or from the intake with food (chylomicrons). The conclusion is, that the enhanced activity of glycerol 3-phosphate dehydrogenase, and hence the generation of more glycerol 3-phosphate in adipose tissue offers a novel explanation for increased TAG production in adipose tissue of obese subjects.

Relationship between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha gene expression in obese human adipose tissue.

To investigate in human adipose tissue a possible relationship between per oxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptor alpha (RARalpha) gene expression, two genes involved in the control of adipocyte differentiation. Ten lean control women (age 31-60 y, body mass index (BMI) 18-24.7 kg/m(2)) and an obese group of 15 women (age 27-62 y, BMI 30-57.5 kg/m(2)), of whom 10 subjects were in weight-gain phase and five were in weight-loss phase. We assessed the relative PPARgamma and RARalpha mRNA levels in subcutaneous abdominal adipose tissue using a real-time PCR method. PPARgamma mRNA level were significantly increased (+91%; P<0.01) in obese women compared to lean control women. In the obese group, we observed a PPARgamma mRNA level 42% lower in weight-loss obese than in weight-gain obese subjects. We obtained a positive correlation (r=0.56; P<0.01) between PPARgamma mRNA level and the BMI of all subjects. Relative mRNA abundance level of RARalpha in subcutaneous adipose tissue of obese subjects is significantly lower than in control subjects (-56%, P<0.01), and a negative correlation was found between PPARgamma and RARalpha mRNA levels in subcutaneous adipose tissue of subjects study (r=-0.75; P<0.01). Our findings suggest that obesity is associated with an inverse relationship between PPARgamma and RARalpha expressions in human subcutaneous adipose tissue. Modulations of nuclear receptor profile could be an important event in the body's early adaptive mechanisms promoting adipose tissue plasticity and leading to the onset of obesity.

Sterol regulatory element binding proteins: relationship of adipose tissue gene expression with obesity in humans

Sterol regulatory element binding proteins (SREBPs) are transcription factors that are involved in adipogenesis and regulate the expression of genes controlling cholesterol and fatty acid biosynthesis. Animal experiments indicate that SREBP-1a, -1c, and -2 have distinct functions despite overlapping specificities for target genes. To study the possible relationships of SREBPs with obesity, we determined their expression levels in intra- and extraperitoneal adipose tissue samples of obese, post-obese and never-obese humans. We furthermore investigated possible associations of SREBP gene expression with mRNA levels of key enzymes of fatty acid and cholesterol biosynthesis. SREBP-1c was the most abundant SREBP mRNA isoform in human adipose tissue. mRNA levels of SREBP-1a and -1c correlated within tissues whereas no correlations were observed between SREBP-1a or -1c and SREBP-2 mRNA abundance. SREBP-1c and -2 mRNA levels were significantly lower in obese than in never-obese and post-obese subjects. SREBP-1c, but not -1a or -2 gene expression was associated with fatty acid synthase and acetyl-CoA carboxylase α gene expression in the intraperitoneal adipose tissue of obese humans. Our results suggest that common mechanisms are involved in the regulation of SREBP-1a and -1c expression in human adipose tissues and imply distinct functions of SREBP isoforms in the regulation of lipid and cholesterol biosynthesis. The reduction in SREBP-1c and -2 mRNA expression in obese humans and their upregulation after weight loss provides new insight into the relationship of these transcription factors with obesity in humans.

Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity.

To determine whether increased lipogenesis contributes to human obesity, we measured (postabsorptive state), in lean and obese subjects, lipid synthesis (deuterated water method) and the mRNA concentration (RT-competitive PCR) in subcutaneous adipose tissue of fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP)-1c. Before energy restriction, obese subjects had an increased contribution of hepatic lipogenesis to the circulating triglyceride pool (14.5 +/- 1.3 vs. 7.5 +/- 1.9%, P < 0.01) without enhancement of cholesterol synthesis. This increased hepatic lipogenesis represented an excess of 2-5 g/day of triglycerides, which would represent 0.7-1.8 kg on a yearly basis. The lipogenic capacity of adipose tissue appeared, on the contrary, decreased with lower FAS mRNA levels (P < 0.01) and a trend for decreased SREBP-1c mRNA (P = 0.06). Energy restriction in obese patients decreased plasma insulin (P < 0.05) and leptin (P < 0.05) and normalized hepatic lipogenesis. FAS mRNA levels were unchanged, whereas SREBP-1c increased. In conclusion, subjects with established obesity have an increased hepatic lipogenesis that could contribute to their excessive fat mass but no evidence for an increased lipogenic capacity of adipose tissue.

Insulin resistance of human adipose tissue in obesity measured with [18F]FDG and PET

Insulin resistance of human adipose tissue in obesity measured with [18F]FDG and PET

Uncoupling protein-2 gene: reduced mRNA expression in intraperitoneal adipose tissue of obese humans.

The mitochondrial uncoupling protein-2 (UCP-2) is a recently discovered homologue of the brown adipose tissue-specific uncoupling protein and could be involved in the regulation of energy balance. Since obesity is associated with disturbed energy homeostasis, we tested the hypothesis that UCP-2 gene expression is deficient in this disorder. We determined, by a competitive reverse transcription-polymerase chain reaction assay, UCP-2 mRNA expression in intra- and extraperitoneal adipose tissues of 107 morbidly obese subjects and 31 lean control subjects. In both obese and non-obese subjects, UCP-2 mRNA abundance was higher in the intraperitoneal than in the extraperitoneal tissue (p < 0.05), but no association was observed between intra- and extraperitoneal expression in either group. Compared with lean control subjects, both male and female obese subjects displayed significantly lower average UCP-2 mRNA expression in the intraperitoneal adipose tissue (p < 0.006), while UCP-2 mRNA abundance in extraperitoneal adipose tissue was not different between obese and non-obese men and women. Intraperitoneal UCP-2 mRNA remained low in nine obese subjects who lost 23 +/- 12 kg of weight over a period of 10 +/- 5 months subsequent to weight reducing surgery. These data support the concept that impaired adipose tissue expression of UCP2 may play a role in the pathophysiology of obesity.

Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue

Insulin resistance in adipose tissue in human obesity is associated with increased protein-tyrosine phosphatase (PTPase) activity and elevated levels of the PTPases leukocyte common antigen-related PTPase (LAR) and PTP1B. To determine whether the improved insulin sensitivity associated with weight loss in obese subjects is accompanied by reversible changes in PTPases, we obtained subcutaneous adipose tissue from seven obese subjects (mean body mass index [BMI], 40.4 kg/m 2) before and after a loss of 10% of body weight and again after a 4-week maintenance period. Weight loss was accompanied by an 18.5% decrease in overall adipose tissue PTPase activity ( P = .015) that was further reduced to 22.3% of the control value ( P = .005) at the end of the maintenance period. By immunoblot analysis, the abundance of LAR was decreased by 21% ( P = .04) and abundance of PTP1B was decreased by 40% ( P < .004) after the initial weight loss, and the decreases persisted during the maintenance period. Enhanced insulin sensitivity following weight loss, evident from a 26% decrease in fasting insulin levels ( P < .05), was also closely correlated with the reduction in the abundance of both LAR ( R 2 = .80, P < .01) and PTP1B ( R 2 = .64, P = .03). These results support the hypothesis that LAR and PTP1B may be reversibly involved in the pathogenesis of insulin resistance, and may be therapeutic targets in insulin-resistant states.

Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids.

The peroxisome proliferator activated receptor (PPAR gamma) plays a key role in adipogenesis and adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin-sensitizing drugs. The tissue expression and potential for regulation of human PPAR gamma gene expression in vivo are unknown. We have cloned a partial human PPAR gamma cDNA, and established an RNase protection assay that permits simultaneous measurements of both PPAR gamma1 and PPAR gamma2 splice variants. Both gamma1 and gamma2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma1 was detected at lower levels in liver and heart, whereas both gamma1 and gamma2 mRNAs were expressed at low levels in skeletal muscle. To examine the hypothesis that obesity is associated with abnormal adipose tissue expression of PPAR gamma, we quantitated PPARgamma mRNA splice variants in subcutaneous adipose tissue of 14 lean and 24 obese subjects. Adipose expression of PPARgamma 2 mRNA was increased in human obesity (14.25 attomol PPAR gamma2/18S in obese females vs 9.9 in lean, P = 0.003). This increase was observed in both male and females. In contrast, no differences were observed in PPAR gamma1/18S mRNA expression. There was a strong positive correlation (r = 0.70, P < 0.001) between the ratio of PPAR gamma2/gamma1 and the body mass index of these patients. We also observed sexually dimorphic expression with increased expression of both PPAR gamma1 and PPAR gamma2 mRNAs in the subcutaneous adipose tissue of women compared with men. To determine the effect of weight loss on PPAR gamma mRNA expression, seven additional obese subjects were fed a low calorie diet (800 Kcal) until 10% weight loss was achieved. Mean expression of adipose PPAR gamma2 mRNA fell 25% (P = 0.0250 after a 10% reduction in body weight), but then increased to pretreatment levels after 4 wk of weight maintenance. Nutritional regulation of PPAR gamma1 was not seen. In vitro experiments revealed a synergistic effect of insulin and corticosteroids to induce PPAR gamma expression in isolated human adipocytes in culture. We conclude that: (a) human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity.

Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects.

Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.

Influence of age, fat cell weight, and obesity on O2 consumption of human adipose tissue

The oxygen consumption of human adipose tissue (AT) was determined in 53 adults, lean and obese, and in nine lean boys. The oxygen consumption was positively related to fat cell weight and negatively to age and degree of obesity. Men and women did not differ with respect to oxygen consumption of AT. The positive relationship between oxygen consumption per cell and fat cell size was also demonstrated in size-separated cells from the same donors. Expressed per cell the oxygen consumption was higher in fat cells from obese than in cells from lean subjects, but expressed per gram of tissue the opposite result was found. The oxygen consumption of the total AT organ was higher in obese than in lean subjects. The energy expenditure of AT constituted approximately 4% of the estimated 24-h energy expenditure in both groups. It is concluded that obese subjects do not maintain their obesity because of a reduced energy expenditure of the total AT (or of the total body). After a partial weight reduction in five subjects, the energy metabolism tended to change in direction toward the conditions seen in lean subjects. However, it is still an open question whether the observed energy metabolic aberrations of obese human AT are only secondary to the obese state or partly primary and thus of etiological importance.

The antilipolytic effect of insulin in human adipose tissue in obesity, diabetes mellitus, hyperinsulinemia, and starvation

The antilipolytic effect of insulin in vitro was investigated in conditions known to be associated with resistance to the effect of insulin on glucose metabolism. Human subcutaneous adipose tissue was obtained from 14 obese subjects before and during starvation for 7 days, 12 untreated non-insulin dependent diabetics (NIDDM), 6 untreated insulin dependent diabetics (IDDM), and 10 nonobese control subjects. The tissue was incubated with and without insulin in concentration ranging from 1–10.000 μU/ml. Responsiveness (maximum effect) and sensitivity to insulin were determined under basal induction conditions, since insulin had a bimodal effect on noradrenaline stimulated lipolysis. Under normal conditions both insulin sensitivity and insulin responsiveness were positively correlated with the basal rate of lipolysis. In obesity, IDDM and NIDDM there were no change in insulin sensitivity or in insulin responsiveness. When the obese subjects were divided into one hyperinsulinemic group (6 individuals) and one group with normal fasting serum insulin levels (7 individuals) a similar antilipolytic effect of insulin was observed in the two groups. During starvation there was a 20-fold increase in insulin sensitivity ( p < 0.01) but no change in insulin responsiveness in femoral fat and only a decrease in responsiveness ( p < 0.01) in abdominal fat. The present data supports the view that antilipolysis in human fat cells is not involved in the insulin resistance seen in obesity, starvation, diabetes and hyperinsulinemia.

1140 THE EFFECT OF FATTY ACID CHAIN LENGTH IN DIETARY TRIGLYCERIDE ON ADIPOSE TISSUE METABOLISM IN HUMAN SUBJECTS

We have previously demonstrated that the enzymes phosphofructokinase (PFK) and citrate cleavage enzyme (CCE) increase in activity in response to 600 kcal diets in adipose tissue of obese humans while decreasing in lean controls. We have now examined the possible role of different dietary fats since others have shown a decrease in adipose tissue lipogenesis in vivo in rats fed medium chain triglyceride (MCT) when compared to long chain triglyceride (LCT). We compared the effect of dietary LCT and MCT in obese adolescents (n=13) before (weight maintenance;I), during (600 kcals;II), and after (1100 kcals;III) weight reduction. The diets contained 20% of calories as protein, 40% as carbohydrate, and 40% as fat (either 40% LCT or 20% LCT & 20% MCT). Fat samples were obtained weekly and analyzed for PFK, CCE, malic enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PD). During period I there was no difference in enzyme activities when LCT was compared to MCT. During period II CCE was lower on MCT than LCT (3.7 ±2, 12.7±9;p<.05). During period III MCT significantly decreased the activities of PFK (26.0±11, 43.4±10;p<.03) and ME (17.7±7, 32.2±15;p<.04) while increasing the activity of G6PD (33.1±12, 16.0±11;p<.04). The lower activities of ME, CCE, and PFK during MCT diets suggests a dampening effect of the oil on glycolysis and fatty acid synthesis. MCT may be a useful adjunct to weight reduction therapy, especially during the post weight-reduction period when most diets fail.

Suppression of activities of carbohydrate-metabolizing enzymes in adipose tissue of obese humans by clofibrate.

Abstract We studied the effects of insulin, epinephrine, and clofibrate on the activities of carbohydrate-metabolizing enzymes in adipose tissue of 8 obese human volunteer subjects. In all patients, clofibrate decreased the activities of pyruvate kinase, phosphofructokinase, fructose diphosphate aldolase, and fructose diphosphatase after 7 days of treatment. In 4 patients studied in more detail, insulin produced a significant increase in pyruvate kinase and phosphofructokinase activities and a significant decrease in fructose diphosphatase within 5 minutes. Epinephrine injection produced opposite effects. Clofibrate decreased these responses to both insulin and epinephrine. Clofibrate may act at the plasma membrane of the adipose cell to inhibit the lipolytic effects of epinephrine and the antilipolytic effects of insulin.

Glyceride-fatty acid and free fatty acid uptake by human adipose tissue in obesity.

Glyceride-fatty acid and free fatty acid uptake by human adipose tissue in obesity.

Effects of norepinephrine, theophylline and dibutyryl cyclic AMP on in vitro lipolysis of human adipose tissue in obesity.

Lipolysis (release of glycerol and free fatty acids) of subcutaneous human adipose tissuein vitro has been investigated in relation to relative body weight and fat cell size. Studying 86 persons, there was a highly significant logarithmic relation between relative body weight, fat cell size and lipid content of subcutaneous adipose tissue obtained from the abdominal region. Even in extreme obesity a mean fat cell diameter of 135 μ was generally not exceeded. In these cases overweight is due to hypertrophy as well as hyperplasia of adipose tissue. — The basal FFA and glycerol release, calculated on the basis of the lipid content, did not significantly differ in normal and overweight persons. The lipolysis of the individual cell increased, however, with increasing cell diameter. The quotient of resterification (FFA release: glycerol release) was significantly lower in obesity. — When lipolysis was stimulated with norepinephrine, theophylline or dibutyryl-cyclic AMP, the dose response relations were similar in obesity and normal weight. — The stimulation of lipolysis, expressed as % of baseline, was diminished in obesity. Stimulation with dibutyryl-cyclic-AMP was negatively correlated to the cell diameter. — The absolute release of metabolites per fat cell after stimulation with norepinephrine, theophylline or dibutyryl-cyclic AMP was positively correlated with the fat cell diameter. — Addition of glucose resulted in an increment in glycerol release and an inhibition of FFA release. However, the correlation of lipolysis with fat cell diameter was not affected. — The observations suggest that large fat cells are provided with additional total lipase. Under basal conditions the relation of inactive pro lipase to active lipase seemed to change in favour of the active enzyme.

The glucose uptake of human adipose tissue in obesity.

Abstract. Radioactivity in adipose tissue triglycerides was followed after giving an intravenous injection of 25 g of glucose with 50 μCi of U‐14C‐glucose to 12 obese and 7 control patients. Seventy‐five minutes after injection the radioactivity could be measured with sufficient precision. Recirculation of label was probably small during this period. Total adipose tissue glucose uptake could therefore be estimated knowing the variation of adipose tissue triglyceride radioactivity in different selected regions, and total body fat, and was found to be only a few per cent of all assimilated glucose in the body. Triglyceride radio‐activity per gram of adipose tissue was similar in obese subjects and controls. Consequently total adipose tissue label was higher in the obese. Triglyceride radioactivity per fat cell correlated positively with fat cell size which in turn correlated positively with plasma insulin concentration. During the two first weeks after injection adipose tissue triglyceride radioactivity increased after which it began to fall in some patients.

The half-life of triglycerides labeled from glucose in subcutaneous adipose tissue in human obesity. A preliminary report

The half-life of triglycerides labeled from glucose in subcutaneous adipose tissue in human obesity. A preliminary report

Influence of norepinephrine, growth hormone and fasting on FFA mobilization and glucose metabolism in lean and obese subjects.

The influence of norepinephrine (NE), human growth hormone (HGH) and fasting on FFA mobilization and carbohydrate metabolism has been studied in 47 obese females and 72 nonobese control subjects (35 females and 37 males). — Weight-related doses of NE infused for 2 h (0.1 γ/kg/min) induced a much greater rise in plasma FFA and blood glucose concentrations in obese than in normal subjects. With a fixed dose (10 γ/min for 2 h), FFA response was still significantly higher in the overweight than in the lean subjects, while glucose reponses were similar in both groups. Among the control subjects, males and females behaved similarily. — The plasma FFA rise observed in the 4 h following thei. v. injection of HGH (10 mg) was not statistically different in obese females, normal males and normal females. — These results suggest that human obese adipose tissue has no impaired sensitivity toward the lipolytic action of NE and HGH. — During fasting, obese, when compared with normal subjects, showed a smaller increase in plasma FFA level together with a smaller decrease in glucose flux. The possible relationship between these 2 anomalies is discussed, considering that glucose deficiency has a major role in regulating FFA mobilization during fasting.

Metabolism of α-Glycerol Phosphate in Human Adipose Tissue in Obesity1

ABSTRACT 1. 1. Experiments were carried out to examine the possibility that a metabolic defect underlies the development of some types of obesity in man. Glycerol phosphate, which is an obligatory acyl acceptor for lipogenesis in human adipose tissue, is formed by a cytoplasmic L-aglycerophosphate dehydrogenase whose activity in adipose tissue of lean and obese patients was, respectively: 36 ± 4 (7)3 and 20 ± 2 (7) mμxmoles NADH/min/mg protein (p <.01). 2. 2. α-Glycerol phosphate can be oxidized by mitochondria of human adipose tissue at a rate of: 14.2 ± 2.2 (8) and 6.9 ± 1.8 (7) μl O2/30 min/mg protein in lean and obese patients, respectively (p < 0.02). Since α-glycerol phosphate is present oxidation of α-glycerol phosphate by mitochondria contributes in part to the development of obesity by increasing the supply of α-glycerol phosphate for lipogenesis. 3. 3. Not all obese patients displayed this mitochondrial deficiency. Three patients were studied in whom an intracranial lesion was possibly responsib...