Adipocytes as regulators of energy balance and glucose homeostasis

Abstract

Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.

Figure 1. Energy homeostasis depends upon the balance between caloric intake and energy expenditure

Although caloric intake is almost entirely due to the consumption of food (minus whatever fails to be absorbed), energy expenditure has more components, including basal metabolism, physical activity (voluntary and involuntary) and adaptive thermogenesis. The last category includes the small amount of energy spent in absorbing and processing the diet (known as diet-induced thermogenesis) as well as energy spent to maintain body temperature in the face of cold.

Figure 2. Adipocytes regulate energy balance by endocrine and non-endocrine mechanisms

Adipocytes synthesize and secrete leptin, which circulates in the blood and acts on the CNS (primarily the hypothalamus) to reduce food intake and enhance energy expenditure. Adipose tissue also communicates with the CNS by means of a rich network of peripheral nerves, which can transmit afferent signals about energy status to the brain, such as when UCP-1 is expressed ectopically. This results in enhanced leptin sensitivity, which increases the effect of secreted leptin on energy balance.

Figure 3. Glucose homeostasis requires the coordinated actions of various organs

Inputs to serum glucose levels include absorption from the intestine and release from the liver. The latter occurs by breakdown of preformed glycogen as well as gluconeogenesis, and both processes are inhibited by insulin. Glucose is removed from the system by uptake into virtually all cell types, but most importantly into muscle and adipose tissue, which requires insulin. Recent evidence suggests that the CNS can also sense glucose and act to affect systemic glycaemia, at least in part by regulating gluconeogenesis.

Figure 4. Adipocytes secrete proteins with varied effects on glucose homeostasis

Adipocyte-derived proteins with anti-diabetic action (green arrows) include leptin, adiponectin, omentin and visfatin. Other factors tend to raise blood glucose (red arrows), including resistin, TNF-α and RBP4. TNF-α and human resistin are probably secreted by non-adipocytes within the fat pad. IL, interleukin.

Figure 5. Adipocyte-derived non-esterified fatty acids have several effects on glucose homeostasis

Lipolysis in adipocytes is repressed by insulin, so it is normal in the fasted state when insulin levels are low. Insulin resistance, however, is also associated with lipolysis and NEFA release into the circulation. Elevated serum NEFAs inhibit insulin’s ability to promote peripheral glucose uptake into muscle and fat and to reduce hepatic glucose production. Transiently elevated NEFAs (such as occur after a meal) tend to enhance insulin secretion, whereas chronic elevations in NEFAs (such as occur in insulin resistance) tend to reduce insulin secretion.