OBJECTIVE: Administration of FGF21 to mice reduces body weight and increases body temperature. The increase in body temperature is generally interpreted as hyperthermia, i.e. a condition secondary to the increase in energy expenditure (heat production). Here, we examine an alternative hypothesis: that FGF21 has a direct pyrexic effect, i.e. FGF21 increases body temperature independently of any effect on energy expenditure. METHODS: We studied the effects of FGF21 treatment on body temperature and energy expenditure in high-fat-diet-fed and chow-fed mice exposed acutely to various ambient temperatures, in high-fat diet-fed mice housed at 30 °C (i.e. at thermoneutrality), and in mice lacking uncoupling protein 1 (UCP1). RESULTS: In every model studied, FGF21 increased body temperature, but energy expenditure was increased only in some models. The effect of FGF21 on body temperature was more (not less, as expected in hyperthermia) pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct (daytime versus nighttime). FGF21 enhanced UCP1 protein content in brown adipose tissue (BAT); there was no measurable UCP1 protein in inguinal brite/beige adipose tissue. FGF21 increased energy expenditure through adrenergic stimulation of BAT. In mice lacking UCP1, FGF21 did not increase energy expenditure but increased body temperature by reducing heat loss, e.g. a reduced tail surface temperature. CONCLUSION: The effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and can be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.
- Klíčová slova
- Beiging/browning, Body temperature control, Obesity, Thermoneutrality, UCP1,
- MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- energetický metabolismus účinky léků MeSH
- fibroblastové růstové faktory aplikace a dávkování farmakologie MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- tělesná teplota účinky léků MeSH
- uncoupling protein 1 nedostatek metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fibroblast growth factor 21 MeSH Prohlížeč
- fibroblastové růstové faktory MeSH
- Ucp1 protein, mouse MeSH Prohlížeč
- uncoupling protein 1 MeSH
The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
- Klíčová slova
- glucagon, insulin receptor antagonist, leptin, thermoneutrality, type 1 diabetes, uncoupling protein 1,
- MeSH
- bílá tuková tkáň metabolismus MeSH
- diabetes mellitus 1. typu metabolismus MeSH
- experimentální diabetes mellitus metabolismus MeSH
- glukagon metabolismus MeSH
- glukoneogeneze MeSH
- hnědá tuková tkáň metabolismus MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- inzulin metabolismus MeSH
- kortikosteron metabolismus MeSH
- krevní glukóza účinky léků metabolismus MeSH
- kyselina pyrohroznová metabolismus MeSH
- leptin metabolismus farmakologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- peptidy farmakologie MeSH
- přijímání potravy MeSH
- receptor inzulinu antagonisté a inhibitory MeSH
- spotřeba kyslíku MeSH
- transkriptom MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukagon MeSH
- insulin-like growth factor-1, mouse MeSH Prohlížeč
- insulinu podobný růstový faktor I MeSH
- inzulin MeSH
- kortikosteron MeSH
- krevní glukóza MeSH
- kyselina pyrohroznová MeSH
- LEP protein, human MeSH Prohlížeč
- leptin MeSH
- peptidy MeSH
- receptor inzulinu MeSH
- S961 peptide MeSH Prohlížeč
- Ucp1 protein, mouse MeSH Prohlížeč
- uncoupling protein 1 MeSH
