Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice
| Autor: | Kamal Rahmouni, Eleftheria Maratos-Flier, Eleen Zarebidaki, Jeffrey S. Flier, Theodore I. Cisu, Ngoc Ly T. Nguyen, Bhavna N. Desai, ffolliott M. Fisher, Alan J. Fowler, Donald A. Morgan, Nicholas Douris, Timothy J. Bartness |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
SNS sympathetic nervous system Male Weight loss FGF21 Sympathetic Nervous System medicine.medical_treatment FGF21 fibroblast growth factor 21 Mice KD ketogenic diet Brown adipose tissue SNA sympathetic nerve activity IWAT inguinal white adipose tissue β-less lacking β1 β2 β3 adrenergic receptors Receptor Ketogenic diet Adaptation Physiological Receptors Adrenergic medicine.anatomical_structure Liver Mice Inbred DBA Original Article IP intraperitoneal Diet Ketogenic lcsh:Internal medicine medicine.medical_specialty Adrenergic receptor Alpha (ethology) Biology SEM standard error of the mean 03 medical and health sciences Internal medicine UCP1 uncoupling protein 1 medicine Animals β-Adrenergic receptors lcsh:RC31-1245 Molecular Biology ITT insulin tolerance test PPARα peroxisome proliferator-activated receptor alpha Insulin EE energy expenditure Cell Biology medicine.disease BAT brown adipose tissue Fibroblast Growth Factors Mice Inbred C57BL 030104 developmental biology Endocrinology Ketosis |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 6, Iss 8, Pp 854-862 (2017) |
| ISSN: | 2212-8778 |
| Popis: | Objective We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis. Methods To test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding. Results In contrast to wild-type (WT) controls, β-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, β-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of β-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and β-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed β-less mice. Conclusions The response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms. Highlights • Ketogenic diets lead to rapid increases in energy expenditure via increased sympathetic outflow to BAT. Long term the diet leads to weight loss. • β-adrenergic receptors mediate these effects; in mice lacking all three β-receptors the effects of the ketogenic diet are not observed. • Browning of subcutaneous fat by the diet is partially activated by presumed peripheral mechanisms in the absence of β-adrenergic receptors. • Sympathetic nervous system activity not required for improved insulin sensitivity and activation of fatty acid oxidation in the liver. |
| Databáze: | OpenAIRE |
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