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  • A 77-01 Multiple mechanisms have been suggested by

    2021-09-14

    Multiple mechanisms have been suggested by which glucagon can increase energy expenditure although none have been conclusively proven to be responsible. Both enhanced gluconeogenesis and enhanced protein turnover secondary to hyperglucagonaemia have been suggested as the reason for the increased metabolic rate in people with diabetes [41], [42], [43]. It has also been suggested that glucagon enhances energy expenditure via increased brown adipose tissue activation. In vitro, glucagon enhances oxygen uptake, heat production and fatty A 77-01 release in brown adipocytes [44], [45]. In vivo, it increased oxygen consumption in rats while enhancing blood flow to brown adipose tissue, it increased GDP binding to mitochondria in BAT and increased BAT weight [46], [47], [48]. However, these are all indirect measures of BAT activity, and more recently, a study using thermal imaging has shown no increase in BAT thermogenesis in man during a glucagon infusion, despite a contemporaneous increase in energy expenditure [27]. Further studies are therefore required to determine how glucagon increases energy expenditure. With regards to OXM, few mechanisms for its increase in energy expenditure have been posited. Though ICV OXM has been shown to increase sympathetic nerve discharge to BAT and increased UCP-1 levels, there is no evidence that this leads to enhanced oxygen consumption or clinically relevant weight loss. There is no data on protein turnover following oxyntomodulin administration, and the data on gluconeogenesis is conflicting, with some studies showing increased expression of gluconeogenic enzymes following OXM analogue administration, and other studies showing no changes [14], [15], [49]. Dual and even triple agonist therapies combining GLP-1, GIP and glucagon receptor activities are being actively trialled for obesity and diabetes [17], [50], [51], [52]. Many other drugs which increase energy expenditure have been withdrawn as treatments for obesity due to side effects (for example dinitrophenol for its hepatic toxicity; amphetamines and levothyroxine for their cardiovascular side effects). To develop safe and efficacious treatments for obesity, it is essential to understand how these dual/triple receptor agonists increase energy expenditure, therefore further mechanistic studies in this field are essential.
    Funding The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7- HEALTH- 2009-241592 EuroCHIP grant and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the author(s) and not necessarily those of the funders, the NHS, the NIHR or the Department of Health. R. Scott is also funded by the Wellcome Trust.
    Introduction The proglucagon-derived peptides (PGDPs) are encoded by a single mammalian gene and include glucagon (GCG), oxyntomodulin, glicentin, and two GCG-like peptides, GLP-1 and GLP-2 [1]. The PGDPs control energy intake, gut motility, mucosal integrity, and the absorption, disposal and storage of ingested energy. The prototype member of the PGDP family, 29 amino acid GCG, is produced in and secreted from islet α-cells, and to a lesser extent, from brainstem neurons [1]. The principal biological role of pancreatic GCG is the maintenance of euglycemia through its control of hepatic glucose production [2], [3], [4]. GCG exerts its metabolic actions through a single GCG receptor (GCGR) [5] highly expressed in hepatocytes but also detected in brain, heart, kidney, gastrointestinal tract, and both white and brown adipose tissue (WAT and BAT, respectively) [6], [7]. Although less extensively studied, GCG exerts direct actions on adipose tissue, encompassing increased blood flow, stimulation of lipolysis, increased glucose uptake and increased oxygen consumption in WAT and BAT [8], [9], [10], [11], [12]. In addition, GCG administration also acutely increases whole body oxygen consumption following administration to animals and humans in vivo [13], [14], [15].