Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo

Abstract

Our aims were to further characterize the stimulatory effect of glucagon on brown fat and to test the hypothesis that physiological levels of hyperglucagonemia would stimulate brown fat thermogenesis. In the first set of experiments, glucagon (1 mg/kg sc twice daily) or vehicle control was administered three times in 26 h. This large dose of glucagon produced increases in GDP binding to brown fat mitochondria. In addition, Scatchard analysis indicated a glucagon-induced increase in number of GDP binding sites without evidence for alteration in binding site affinity. No consistent increase in brown fat mitochondrial GDP binding was produced 2 h after a single injection of glucagon (1 mg/kg). In the second set of experiments, glucagon was administered intraperitoneally by constant osmotic minipump infusion. Glucagon in a dose of 150 micrograms.kg-1.day-1 for 5 days produced significant increases in GDP binding to brown fat mitochondria, whereas glucagon serum levels were increased but stayed within the usual physiological range. A larger dose of glucagon administered by constant infusion virtually eliminated body weight gain over 7 days while significantly increasing nucleotide binding (GDP) to brown fat mitochondria. An important role for glucagon in thermogenic regulation is suggested.

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

“…Consistent with a role in modulating food intake, glucagon also appears to affect the regulation of body weight by promoting weight loss in physiological and pathological doses as observed in patients with glucagonoma (Schulman et al 1957, Bloom & Polak 1987. In addition, rodent models and in vitro studies have demonstrated that glucagon increases energy expenditure through activation of brown adipose tissue (Billington et al 1991).…”

Coinfusion of Low-Dose GLP-1 and Glucagon in Man Results in a Reduction in Food Intake

“…The mechanism behind the increase in REE mediated by glucagon remains unclear. This phenomenon could be mediated by increased thermogenesis in brown adipose tissue (6) and/or by futile substrate cycling (43). These effects may be direct, via tissue glucagon receptor (e.g., in brown adipose tissue), or indirect, via an increase in catecholamines (44).…”

“…Glucagon has been shown to potently increase satiety and acutely reduce food intake in humans (3). Additionally, glucagon has the ability to significantly increase energy expenditure during infusion in man (4,5) and has been reported to promote nonshivering thermogenesis in brown adipose tissue in rodents (6). Appetite inhibition classically results in defense of body weight by a reduction of energy expenditure (7,8).…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…However, the glucocentric view of glucagon overshadows the other beneficial effects that it could serve beyond glucose management . Glucagon acts on the brain to decrease food intake (Salter, 1960;de Castro et al, 1978;Billington et al, 1991); it increases energy expenditure through stimulation of brown fat thermogenesis (Joel, 1966;Kuroshima and Yahata, 1979;Doi and Kuroshima, 1982), inhibits gastric motility (Watanabe et al, 1982;Mochiki et al, 1998;Shibata et al, 2001), decreases fat accumulation via stimulation of lipolysis and inhibition of lipid synthesis (Caren and Corbo, 1960;Salter et al, 1960;Paloyan and Harper, 1961;Amatuzio et al, 1962;De Oya et al, 1971;Eaton, 1973), can improve cardiac performance (Whitehouse and James, 1966;726 Glick et al, 1968;Laraia et al, 1968;Lucchesi, 1968;Katz et al, 1969), and stimulates autophagy (Deter and De Duve, 1967;Arstila and Trump, 1968;Guder et al, 1970;Deter, 1971). Collectively, these nonglycemic effects render glucagon an interesting candidate for pharmacological management of body weight.…”