Circulating and local catecholamines are elevated in high fat diet induced adipose catecholamine resistance

Catecholamines such as epinephrine and norepinephrine regulate white adipose tissue lipolysis through β-adrenergic receptors (β-AR). In metabolic syndrome, adipose tissue downregulates β-AR and becomes catecholamine resistant, a finding recapitulated under high-fat diet. In many receptor-ligand systems, chronic stimulation induces desensitization, but limited data explores whether this relationship holds true for adipose tissue catecholamine resistance. Catecholamine signaling in adipose tissue is also regulated by clearance through monoamine oxidases and catechol-O-methyltransferases, but almost no data have examined the products of these pathways in adipose tissue. We show that plasma catecholamines are elevated under short term high fat diet in male mice prior to onset of catecholamine resistance at two weeks of HFD. At eight weeks of HFD, circulating catecholamines remain elevated and correlate with visceral mesenteric and subcutaneous fat mass accrual. Catecholamine elevations co-occur with catecholamine resistance in both fat pads, which we demonstrate is receptor dependent and is alleviated by bypassing β-AR using forskolin. We also observe elevated adipose tissue norepinephrine turnover without any change in its downstream metabolites, dihydroxyphenylglycol (DHPG) or 3-Methoxy-4-hydroxyphenylglycol (MHPG), suggestive of unchanged neurotransmitter clearance and increased norepinephrine availability driven by increased secretion. Inhibiting monoamine oxidase A mediated norepinephrine clearance using moclobemide blunted energy expenditure responses to Cl314,243, the β3-AR agonist. Taken together, these data suggest that elevated catecholamines could be causally related to catecholamine resistance and suggest a novel approach to reversing catecholamine resistance by increasing clearance or decreasing receptor stimulation.