AI Article Synopsis

  • The study explores how a low-carbohydrate ketogenic diet (KD) affects mice, showing that it promotes weight loss and improved insulin sensitivity, with FGF21 being a crucial mediator.
  • Researchers tested mice lacking β-adrenergic receptors and found that these mice gained weight and did not increase energy expenditure while on a KD but remained insulin sensitive.
  • Results indicate that while FGF21 influences liver metabolism independent of the sympathetic nervous system, the activation of energy expenditure in brown adipose tissue requires signals from the sympathetic nervous system through β-adrenergic receptors.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518722PMC
http://dx.doi.org/10.1016/j.molmet.2017.05.017DOI Listing

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