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Lipid metabolism is essential for growth and generates much of the energy needed during periods of starvation. In Drosophila, fasting larvae release large quantities of lipid from the fat body but it is unclear how and where this is processed. Here we identify the oenocyte as the principal cell type accumulating lipid droplets during starvation. Tissue-specific manipulations of the Slimfast amino-acid channel, the Lsd2 fat-storage regulator and the Brummer lipase indicate that oenocytes act downstream of the fat body. In turn, oenocytes are required for depleting stored lipid from the fat body during fasting. Hence, lipid-metabolic coupling between the fat body and oenocytes is bidirectional. When food is plentiful, oenocytes have critical roles in regulating growth, development and feeding behaviour. In addition, they specifically express many different lipid-metabolizing proteins, including Cyp4g1, an omega-hydroxylase regulating triacylglycerol composition. These findings provide evidence that some lipid-processing functions of the mammalian liver are performed in insects by oenocytes.

The lower insulin excursion after fructose may result in less activation of adipose tissue lipoprotein lipase, which led to impaired triacylglycerol clearance. The contribution of de novo lipogenesis to fructose-induced hypertriacylglycerolemia is small, but its effect on altering the partitioning of fatty acids toward esterification may be considerable.

OBJECTIVELipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.RESEARCH DESIGN AND METHODSTo investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).RESULTSAbdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.CONCLUSIONSEnlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

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OBJECTIVE-Pharmacological use of peroxisome proliferatoractivated receptor (PPAR)␦ agonists and transgenic overexpression of PPAR␦ in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS-The, and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS-Treatment with GW501516showed statistically significant reductions in fasting plasma triglycerides (Ϫ30%), apolipoprotein B (Ϫ26%), LDL cholesterol (Ϫ23%), and insulin (Ϫ11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P Ͻ 0.05) and 30% reduction in urinary isoprostanes (P ϭ 0.01) were also observed. Except for a lowering of triglycerides (Ϫ30%, P Ͻ 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased (P Ͻ 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased.CONCLUSIONS-The PPAR␦ agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle. Diabetes 57: 332-339, 2008

Current British dietary recommendations are to reduce total fat intake to less than 30 % of total energy intake and saturated fat to less than 10 %. The energy lost by this suggested decrease in saturated fat intake is partially replaced by increasing polyunsaturated fat intake. A high intake of total dietary fat has been shown to cause fasting hyperinsulinaemia [1] and to reduce the ability of insulin to suppress endogenous glucose production [2]. Dietary studies have, however, provided conflicting evidence about the beneficial effects of a diet rich in polyunsaturated fat (PUFA diet) on lipoprotein and glucose metabolism.In non-diabetic subjects a PUFA diet could improve total plasma cholesterol concentrations [3] but this could be at the expense of a decrease in HDLcholesterol [4]. On the other hand, in patients with Diabetologia (2002) Abstract Aims/hypothesis. British dietary recommendations are to decrease total fat intake to less than 30 % of daily energy intake and saturated fat to less than 10 %. In practice, it is difficult for people to make these changes. It may be easier to encourage people to switch from a diet rich in saturated fatty acids to one rich in polyunsaturated fatty acids. Methods. A total of 17 subjects ± six people with Type II (non-insulin-dependent) diabetes mellitus, six nonobese and five obese people without diabetes ± were randomised to spend two 5-week periods on a diet rich in saturated or in polyunsaturated fatty acids, in a crossover design. At the start of the study and after each dietary period, we assessed abdominal fat distribution using magnetic resonance imaging, insulin sensitivity using hyperinsulinaemic-euglycaemic clamps and fasting lipid parameters.Results. Dietary compliance, assessed by weekly 3-day dietary records and measurement of biochemical markers, was good. Energy and fat intake appeared to be reduced on the diet rich in polyunsaturated fatty acids although body weights did not change. Insulin sensitivity and plasma low density lipoprotein cholesterol concentrations improved with the diet rich in polyunsaturated fatty acids compared with the diet rich in saturated fatty acids. There was also a decrease in abdominal subcutaneous fat area. Conclusion/interpretation. If this result is confirmed in longer-term studies, this dietary manipulation would be more readily achieved by the general population than the current recommendations and could result in considerable improvement in insulin sensitivity, reducing the risk of developing Type II diabetes. [Diabetologia (2002) 45: 369±377]

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