Mechanisms of catecholamine effects on ketogenesis

Abstract

Ketogenesis may be controlled at several sites. Lipolysis with release of plasma nonesterified fatty acid (NEFA) substrate is the first step. Plasma NEFA are taken up by the liver in a concentration-dependent fashion and, after conversion to the acyl-CoA derivative, may either be reesterified or enter the mitochondria via the carnitine shuttle. After beta-oxidation the resultant acetyl-CoA may either be converted to ketone bodies that are then released into the circulation or be condensed with oxaloacetate and enter the tricarboxylic acid cycle, the third potential control point. In humans, infusion of epinephrine causes a transient two- to threefold increase in fatty acids, glycerol, and ketone bodies. Insulin levels show a small absolute increase. Norepinephrine has similar effects, although insulin levels tend to be suppressed and glucagon levels rise somewhat. If somatostatin is added simultaneously, the lipolytic and ketogenic effects are accentuated and prolonged. Dopamine, in a high dose, has no effect on ketone bodies alone but shows small increases in NEFA and ketone bodies in the presence of somatostatin and may play a modulatory role in ketogenesis. The ketogenic effect of catecholamines could thus be in the adipocyte or in the liver. Studies with perfused liver or hepatocytes showed only trivial effects on ketogenesis even with supraphysiological doses of catecholamines. Furthermore infusion studies in rats showed decreased rather than increased ketogenesis with no change in NEFA levels. The data suggest that a) there are species differences, and b) in humans epinephrine- and norepinephrine-induced increases in ketogenesis are secondary to increases in NEFA substrate supply.

Activation of Peroxisome Proliferator-Activated Receptors (PPARs) by Their Ligands and Protein Kinase A Activators

“…Stress, fasting, or exercise are also associated with an increased glucagon production (one of the key factors increasing cAMP levels in cells and thus activating PKA) by the adrenal gland (50). PKA increases PPAR␣ activity in liver, which in turn stimulates the ␤-oxidation and in particular the conversion of FA into acetyl-CoA used in the production of ketone bodies (51). Results from our laboratory (52) have also demonstrated that fasting did not affect FABP expression in WT mice.…”

Epinephrine deficiency results in intact glucose counter-regulation, severe hepatic steatosis and possible defective autophagy in fasting mice

“…Epinephrine has been thought to have a secondary role in metabolic regulation in the presence of an intact glucagon response (Cryer, 1993a,b). In humans, epinephrine infusion results in enhanced lipolysis and a rise in free fatty acids, glycerol and ketone levels independently of insulin and glucagon (Bahnsen et al, 1984), an effect blocked by propranolol (Rizza et al, 1980). Propranolol is a non-selective adrenergic antagonist that blocks the effect of both epinephrine and norepinephrine.…”

Regulation of Ketone Body Metabolism and the Role of PPARα

“…Increased influx of fatty acids to the liver induces their β-oxidation and subsequent ketogenesis. Among catabolic hormones, epinephrine and norepinephrine, which drive “fight or flight” reactions to stress, are particularly strong activators of lipolysis, fatty acid oxidation and ketogenesis, and remain active regardless of insulin levels [8,9]. …”