Beta-adrenergic receptors are critical for weight loss
but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice.
Mol Metab. 2017 08;6(8):854-862
Authors: Douris N, Desai BN, Fisher FM, Cisu T, Fowler AJ, Zarebidaki E, Nguyen NLT, Morgan DA, Bartness TJ, Rahmouni K, Flier JS, Maratos-Flier E
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 . 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 . FGF21 activates the sympathetic nervous system (SNS) , 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.
PMID: 28752049 [PubMed - indexed for MEDLINE]