β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

Abstract

With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β3-adrenergic receptors. However, vast majorities of β3-adrenergic agonists have so far not been able to stimulate human β3-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β1-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β3-adrenergic receptors. Wild-type and β3-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β3-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β1-adrenergic receptors. Thus, in the absence of β3-adrenergic receptors, β1-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β1-adrenergic receptors or β3-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β1-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

“…Currently available β3-AR agonists have high efficacy in murine cells transfected with human β3-AR and can activate UCP-1 in human-derived differentiated brown adipocytes. 95 However, treatment of humans with a β3-AR agonist showed no effects 96 or minor effects 97,98 Figure 2. Brown adipose tissue (BAT) activation reduces hypercholesterolemia and atherosclerosis development.…”

MECHANISMS IN ENDOCRINOLOGY: Brown adipose tissue in humans: regulation and metabolic significance

“…There are three types of b-ARs (b 1 , b 2 and b 3 ), all of which are expressed in BAT (52,53,54,55). b 3 is the predominant b-AR in BAT of rodents (54,55).…”

“…b 3 is the predominant b-AR in BAT of rodents (54,55). In contrast, b 1 and b 2 are more abundant than b 3 in human brown adipocytes (52,53). Propranolol, a beta-blocker with predominant action on b 1 and b 2 and poor efficacy for b 3 , abolishes BAT activity seen on FDG-PET scan in humans (56,57).…”

Stimulation of Thermogenesis via Beta-Adrenergic and Thyroid Hormone Receptors Agonists in obesity Treatment – Possible Reasons for Therapy Resistance

“…Although targeted disruption of the adrb2 gene does not impair cold-and dietinduced thermogenesis in mice and seems to have no influence body weight, adiposity and lipids metabolism, it impairs glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion [18]. Similarly, mice with adrb3 knockout, due to the normal function of the ADRB1, are able to maintain core body temperature in cold but their resting metabolic rate is lower compared to wild-type controls that predispose them to obesity [19].…”

“…The in vitro studies performed on human multipotent adipocyte-derived stem cells suggest that activation of ADRB3 receptors by a selective agonist (CL-316243) leads to the increased UCP1 mRNA synthesis and differentiation towards brown adipocytes [19]. In rodents, ADRB3 ligands induce intense thermogenic and lipolytic response that results in the loss of fat mass without affecting the lean body mass and in the subsequent improvement of glucose control [47].…”