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Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice
Journal article   Open access   Peer reviewed

Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice

Nicholas Douris, Bhavna N Desai, ffolliott M Fisher, Theodore Cisu, Alan J Fowler, Eleen Zarebidaki, Ngoc Ly T Nguyen, Donald A Morgan, Timothy J Bartness, Kamal Rahmouni, …
Molecular metabolism (Germany), Vol.6(8), pp.854-862
08/2017
DOI: 10.1016/j.molmet.2017.05.017
PMCID: PMC5518722
PMID: 28752049
url
https://doi.org/10.1016/j.molmet.2017.05.017View
Published (Version of record) Open Access

Abstract

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. To test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding. 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. 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. •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.
 Sympathetic nervous system β-Adrenergic receptors Ketogenic diet Weight loss

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