| First Author | Douris N | Year | 2017 |
| Journal | Mol Metab | Volume | 6 |
| Issue | 8 | Pages | 854-862 |
| PubMed ID | 28752049 | Mgi Jnum | J:277948 |
| Mgi Id | MGI:6274175 | Doi | 10.1016/j.molmet.2017.05.017 |
| Citation | Douris N, et al. (2017) 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 6(8):854-862 |
| abstractText | 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 beta-adrenergic receptors (beta-less mice) to KD feeding. RESULTS: In contrast to wild-type (WT) controls, beta-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, beta-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of beta-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and beta-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 beta-less mice. CONCLUSIONS: The response of beta-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 (PPARalpha)-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 beta-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms. |
