Adipose (fat) Tissue Lipid Chaperone, aP2, Regulates Liver Glucose Homeostasis
Adipose tissue is much more than just the fat storage organ. Mature adipocytes synthesize and secrete numerous enzymes, growth factors, cytokines (referred to as adipokines) and hormones that are involved in overall whole body energy homeostasis. There are currently over 50 different adipokines recognized as being secreted from adipose tissue. These adipokines are implicated in the modulation of a range of physiological responses that globally includes appetite control and energy balance. Specific metabolic processes regulated by adipose tissue include lipid metabolism, glucose homeostasis, inflammation, angiogenesis, hemostasis, and blood pressure. For more details on the functions of adipose tissue go to the Adipose Tissue: Not Just Fat page of my website
Indeed, adipose tissue is a critical organ for storage of energy in the form of triglycerides. Upon hormonal demand the fatty acids f triglycerides are released to the circulation where they can by absorbed by other tissues and oxidized to produce needed ATP. The processes of lipid storage and release from adipose tissue are complex and involve numerous proteins and enzymes associated with the fat droplets inside adipocytes. New evidence, just recently published in the journal Cell Metabolism, demonstrates that a protein that was once thought to have a primary function as a lipid chaperone within adipocytes (the fatty acid binding protein called aP2, also called fatty acid binding protein 4, FABP4) is actually also a secreted factor of adipose tissue and that when secreted exerts effects on the liver leading to increased glucose output.
Adipocyte Lipid Chaperone aP2 Is a Secreted Adipokine Regulating Hepatic Glucose Production
As a brief background, intracellular fatty acid homeostasis involves a number of factors and two of these in adipose tissue are the adipose fatty acid binding proteins (FABPs) aP2 (FABP4) and FABP5, where aP2 is the major binding protein in this tissue. Previous experiments have demonstrated that mice deļ¬cient in these lipid chaperones are protected against many of the metabolic abnormalities associated with obesity. Also, previous experiments by the authors of the above linked manuscript have shown that aP2 deficient adipose tissue results in altered glucose production by the liver. These observations showed that the effects were not due to leptin or adiponectin, two of the major adipose tissue hormones.
The current publication shows that aP2 is secreted from adipose tissue in response to fasting and that this secretion results in regulation of hepatic glucose production. In the experimental mice, depletion of serum aP2 results in suppression of hepatic glucose production, whereas, elevation of serum aP2 in these mice leads to enhanced hepatic glucose production. Of clinical significance to humans is that aP2 secretion and serum levels are positively correlated with obesity.
The results of this publication demonstrate that aP2 is actively secreted from adipocytes and then acts on the liver to regulate glucose output. Significantly, the level of aP2 secretion from adipose tissue increases in obesity which leads to further increases in already elevated blood levels of glucose typical of obesity due to obesity-mediated insulin resistance and the development of type 2 diabetes. Of significance to this latter fact is that in experimental mice, neutralization of secreted aP2 results in reduced hepatic glucose output.
aP2 lacks a signal peptide, therefore it is likely that its secretion occurs through a non-classical mechanism. In obesity, adipose tissue inflammation is enhanced and this is associated with cell death (apoptosis) which may contribute to the high levels of aP2 in circulation. Thus, obesity-induced elevations in serum aP2 levels might contribute to the elevated hepatic glucose production, which is the hallmark of hyperglycemia, in subjects with type 2 diabetes typically associated with obesity.
Let me point out the significance of this observation. Adipose tissue expands in obesity and this expansion is associated with increased secretion of pro-inflammatory adipokines. The effects of these inflammatory adipokines are broad and ultimately result in exacerbation of the resistance to insulin which is a major metabolic complication in obesity leading to type 2 diabetes. One of the most significant problems of obesity, insulin resistance, and type 2 diabetes is hyperglycemia. indeed, all of the current pharmacological therapies for type 2 diabetes are aimed at reducing the level of glucose in the blood. So, with an expanding adipose tissue in obesity there is an increased release of aP2 and as a result a further increase in the hyperglycemia due to the stimulation of hepatic glucose production by this adipokine. The observations of this paper indicate that aP2 may very well be another target for pharmacological intervention in the treatment of type 2 diabetes.
Indeed, adipose tissue is a critical organ for storage of energy in the form of triglycerides. Upon hormonal demand the fatty acids f triglycerides are released to the circulation where they can by absorbed by other tissues and oxidized to produce needed ATP. The processes of lipid storage and release from adipose tissue are complex and involve numerous proteins and enzymes associated with the fat droplets inside adipocytes. New evidence, just recently published in the journal Cell Metabolism, demonstrates that a protein that was once thought to have a primary function as a lipid chaperone within adipocytes (the fatty acid binding protein called aP2, also called fatty acid binding protein 4, FABP4) is actually also a secreted factor of adipose tissue and that when secreted exerts effects on the liver leading to increased glucose output.
Adipocyte Lipid Chaperone aP2 Is a Secreted Adipokine Regulating Hepatic Glucose Production
As a brief background, intracellular fatty acid homeostasis involves a number of factors and two of these in adipose tissue are the adipose fatty acid binding proteins (FABPs) aP2 (FABP4) and FABP5, where aP2 is the major binding protein in this tissue. Previous experiments have demonstrated that mice deļ¬cient in these lipid chaperones are protected against many of the metabolic abnormalities associated with obesity. Also, previous experiments by the authors of the above linked manuscript have shown that aP2 deficient adipose tissue results in altered glucose production by the liver. These observations showed that the effects were not due to leptin or adiponectin, two of the major adipose tissue hormones.
The current publication shows that aP2 is secreted from adipose tissue in response to fasting and that this secretion results in regulation of hepatic glucose production. In the experimental mice, depletion of serum aP2 results in suppression of hepatic glucose production, whereas, elevation of serum aP2 in these mice leads to enhanced hepatic glucose production. Of clinical significance to humans is that aP2 secretion and serum levels are positively correlated with obesity.
The results of this publication demonstrate that aP2 is actively secreted from adipocytes and then acts on the liver to regulate glucose output. Significantly, the level of aP2 secretion from adipose tissue increases in obesity which leads to further increases in already elevated blood levels of glucose typical of obesity due to obesity-mediated insulin resistance and the development of type 2 diabetes. Of significance to this latter fact is that in experimental mice, neutralization of secreted aP2 results in reduced hepatic glucose output.
aP2 lacks a signal peptide, therefore it is likely that its secretion occurs through a non-classical mechanism. In obesity, adipose tissue inflammation is enhanced and this is associated with cell death (apoptosis) which may contribute to the high levels of aP2 in circulation. Thus, obesity-induced elevations in serum aP2 levels might contribute to the elevated hepatic glucose production, which is the hallmark of hyperglycemia, in subjects with type 2 diabetes typically associated with obesity.
Let me point out the significance of this observation. Adipose tissue expands in obesity and this expansion is associated with increased secretion of pro-inflammatory adipokines. The effects of these inflammatory adipokines are broad and ultimately result in exacerbation of the resistance to insulin which is a major metabolic complication in obesity leading to type 2 diabetes. One of the most significant problems of obesity, insulin resistance, and type 2 diabetes is hyperglycemia. indeed, all of the current pharmacological therapies for type 2 diabetes are aimed at reducing the level of glucose in the blood. So, with an expanding adipose tissue in obesity there is an increased release of aP2 and as a result a further increase in the hyperglycemia due to the stimulation of hepatic glucose production by this adipokine. The observations of this paper indicate that aP2 may very well be another target for pharmacological intervention in the treatment of type 2 diabetes.
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