Obesity results from an imbalance between lipogenesis (fat synthesis) and lipolysis (fat destruction ). Lipogenesis which occurs in liver and adipose tissue involves fatty acid synthesis followed by triglyceride synthesis. Differentiation of the pre-adipocytes to mature fat cells is referred to as adipogenesis and should not be confused with lipogenesis.
Fasting reduces lipogenesis in adipose tissue producing a reduction of triglycerides in the fat cells. Insulin is a strong inducer of lipogenesis through activation of lipogenic and glycolytic enzymes, as well as by facilitating glucose entry into the adipose tissues by recruiting glucose transporters to the plasma membrane. Insulin also stimulates expression of lipogenic genes via the transcription factor- Sterol Regulatory Element Binding Protein-1 (SREBP-1). Metabolism. 1995 Feb;44(2):228-33. Fasting results in decreased insulin levels with an increase in plasma growth hormone and glucagon. The reduction of insulin in the fasting state can thus be seen to clearly facilitate a reduction in lipogenesis. Lipolysis in the fasting state facilitates further triglyceride loss from the fat cells. These fatty acids are supplied to the liver facilitating increased triglyceride synthesis, even resulting in hepatosteatosis. J Clin Invest. 1999 Jun;103(11):1489-98.
In the fed state in humans (up to 4 hours after a meal), carbohydrates and fat enter the circulation as glucose and chylomicrons. The glucose enters the liver where it is stored as glycogen, and once glycogen stores are replete, the glucose is glycolytically converted to acetyl CoA (promoted by the rising SREBP-1 levels in the fed state) and diverted to synthesis of fatty acids and further into triglycerides and packaged as VLDL. The fatty acid produced from the above process functions as an endogenous ligand for PPAR-γ in the adipose tissue, facilitating triglyceride storage in the adipose tissue. Triglyceride storage increases leptin production in the adipose tissue. Leptin inhibits lipogenesis J Biol Chem. 1999 Jun 18;274(25):17541-4 by decreasing the expression of genes involved in fatty acid and triglyceride synthesis, while stimulating fatty acid oxidation. Genes Dev. 2000 Apr 15;14(8):963-80. Leptin facilitates lipolysis and fatty acid oxidation, processes which are prevented by PPAR-γ mediated negative regulation. When PPAR-γ levels fall, Leptin increases with resultant lower fat storage (and food intake) Mol Cell. 1999 Oct;4(4):597-609.
PPAR α expression which rises in the fasting state J Clin Invest. 1999 Jun;103(11):1489-98. stimulates fatty acid oxidation to Acetyl CoA in the liver and further into ketone bodies (acetoacetate and betahydroxybutyrate).
Growth Hormone reduces lipogenesis in adipose tissue while increasing muscle mass. J Nutr. 2000 Nov;130(11):2623-5. One of the mechanisms may be through blocking insulin signalling at the post receptor level, thus decreasing insulin sensitivity and resultant down-regulation of fatty acid synthase expression in adipose tissue. Growth hormone may also decrease lipogenesis through phosphorylation of the transcription factors Stat5a and 5b. Cell. 1998 May 29;93(5):841-50.
Acyl stimulation protein (ASP) produced from adipose tissue cells, stimulates triglyceride accumulation in adipose cells by increased triglyceride synthesis and decreased adipose tissue lipolysis. Curr Opin Lipidol. 2000 Jun;11(3):291-6 Stimulation of triglyceride synthesis might be mediated by cascades involving phosphodiestrase 3. J Biol Chem. 1999 Jun 25;274(26):18243-51
PUFA (polyunsaturated fatty acids) decrease lipogenesis by suppressing gene expression of fatty acid synthase, and stearoyl-Coa desaturase in the liver. J Lipid Res. 1994 Jun;35(6):1076-84 This down-regulation of gene expression is achieved by inhibiting the m-RNA expression of SREBP-1.
CART infusion increases lipid oxidation in normal and in obese rats. Central injection of CART thus results in increased circulating non-esterified fatty acid (NEFA) levels and decreased lipoprotein lipase activity in adipose tissue. Thus on a fat-rich diet, the Leptin-CART pathway originating in the ARC causes a shift from lipid storage toward lipid mobilization preventing excessive body fat accumulation. Regul Pept. 2004 Feb 15;117(2):89-99
Carbohydrates on the other hand increase lipogenesis in liver and adipose tissue producing elevated post prandial plasma triglyceride levels. Glucose stimulates insulin which is strongly pro-lipogenesis, while suppressing glucagon thus decreasing lipolysis. Glucose is converted via glycolysis to acetyl-CoA which is a substrate for fatty acid synthesis. Glucose also induces expression of lipogenic genes.
Fasting reduces lipogenesis in adipose tissue producing a reduction of triglycerides in the fat cells. Insulin is a strong inducer of lipogenesis through activation of lipogenic and glycolytic enzymes, as well as by facilitating glucose entry into the adipose tissues by recruiting glucose transporters to the plasma membrane. Insulin also stimulates expression of lipogenic genes via the transcription factor- Sterol Regulatory Element Binding Protein-1 (SREBP-1). Metabolism. 1995 Feb;44(2):228-33. Fasting results in decreased insulin levels with an increase in plasma growth hormone and glucagon. The reduction of insulin in the fasting state can thus be seen to clearly facilitate a reduction in lipogenesis. Lipolysis in the fasting state facilitates further triglyceride loss from the fat cells. These fatty acids are supplied to the liver facilitating increased triglyceride synthesis, even resulting in hepatosteatosis. J Clin Invest. 1999 Jun;103(11):1489-98.
In the fed state in humans (up to 4 hours after a meal), carbohydrates and fat enter the circulation as glucose and chylomicrons. The glucose enters the liver where it is stored as glycogen, and once glycogen stores are replete, the glucose is glycolytically converted to acetyl CoA (promoted by the rising SREBP-1 levels in the fed state) and diverted to synthesis of fatty acids and further into triglycerides and packaged as VLDL. The fatty acid produced from the above process functions as an endogenous ligand for PPAR-γ in the adipose tissue, facilitating triglyceride storage in the adipose tissue. Triglyceride storage increases leptin production in the adipose tissue. Leptin inhibits lipogenesis J Biol Chem. 1999 Jun 18;274(25):17541-4 by decreasing the expression of genes involved in fatty acid and triglyceride synthesis, while stimulating fatty acid oxidation. Genes Dev. 2000 Apr 15;14(8):963-80. Leptin facilitates lipolysis and fatty acid oxidation, processes which are prevented by PPAR-γ mediated negative regulation. When PPAR-γ levels fall, Leptin increases with resultant lower fat storage (and food intake) Mol Cell. 1999 Oct;4(4):597-609.
PPAR α expression which rises in the fasting state J Clin Invest. 1999 Jun;103(11):1489-98. stimulates fatty acid oxidation to Acetyl CoA in the liver and further into ketone bodies (acetoacetate and betahydroxybutyrate).
Growth Hormone reduces lipogenesis in adipose tissue while increasing muscle mass. J Nutr. 2000 Nov;130(11):2623-5. One of the mechanisms may be through blocking insulin signalling at the post receptor level, thus decreasing insulin sensitivity and resultant down-regulation of fatty acid synthase expression in adipose tissue. Growth hormone may also decrease lipogenesis through phosphorylation of the transcription factors Stat5a and 5b. Cell. 1998 May 29;93(5):841-50.
Acyl stimulation protein (ASP) produced from adipose tissue cells, stimulates triglyceride accumulation in adipose cells by increased triglyceride synthesis and decreased adipose tissue lipolysis. Curr Opin Lipidol. 2000 Jun;11(3):291-6 Stimulation of triglyceride synthesis might be mediated by cascades involving phosphodiestrase 3. J Biol Chem. 1999 Jun 25;274(26):18243-51
PUFA (polyunsaturated fatty acids) decrease lipogenesis by suppressing gene expression of fatty acid synthase, and stearoyl-Coa desaturase in the liver. J Lipid Res. 1994 Jun;35(6):1076-84 This down-regulation of gene expression is achieved by inhibiting the m-RNA expression of SREBP-1.
CART infusion increases lipid oxidation in normal and in obese rats. Central injection of CART thus results in increased circulating non-esterified fatty acid (NEFA) levels and decreased lipoprotein lipase activity in adipose tissue. Thus on a fat-rich diet, the Leptin-CART pathway originating in the ARC causes a shift from lipid storage toward lipid mobilization preventing excessive body fat accumulation. Regul Pept. 2004 Feb 15;117(2):89-99
Carbohydrates on the other hand increase lipogenesis in liver and adipose tissue producing elevated post prandial plasma triglyceride levels. Glucose stimulates insulin which is strongly pro-lipogenesis, while suppressing glucagon thus decreasing lipolysis. Glucose is converted via glycolysis to acetyl-CoA which is a substrate for fatty acid synthesis. Glucose also induces expression of lipogenic genes.