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  • Ketogenic diets are more effective in promoting weight

    2024-05-14

    Ketogenic diets are more effective in promoting weight loss than conventional caloric restriction [26] however, their effect on hepatic glucose and lipid metabolism remains inconclusive. Blood glucose homeostasis is tightly regulated. In both mice and humans consuming KD, baseline blood glucose decreases and insulin falls dramatically as ketones become the primary fuel for both brain and muscle [14,16]. As a result, systemic insulin requirements decrease in patients with diabetes [15]. Similarly, mice on KD show increased systemic insulin sensitivity as assessed by an insulin tolerance test (ITT) [5]. Therefore, by the parameter of systemic sensitivity, KD consuming mice and humans have increased insulin sensitivity. By contrast, studies in rats [27] and hyperinsulinemic-euglycemic clamp studies in mice [28] have reported that KD causes hepatic insulin resistance at the level of gluconeogenesis and suggested that the diet renders animals overall insulin resistant. Our interpretation of the somewhat conflicting results is that liver insulin resistance results from a long term inactivation of pathways involved in insulin action, which is also seen in diabetic ketoacidosis, a state of complete insulin insufficiency [29]. We speculate that in animals consuming KD, glucose is rapidly utilized by peripheral tissues such as fat and muscle in response to insulin, contributing to reduced serum glucose in the context of low circulating insulin. These beneficial effects on glucose homeostasis are seen in both WT and β-less mice consuming KD, demonstrating that the SNS, and the effects it has on body weight, are dispensable for the observed glucose lowering effects of KD. KD feeding activates transcription factor PPARα in the liver, resulting in hepatic gene expression signatures that promote increased fatty pannexin-1 inhibitor oxidation and reduced fatty acid synthesis [1,2,6,30]. Both WT and β-less mice consuming KD demonstrated an increase in PPARα mediated fatty acid oxidation enzymes CPT1α, CPT1β, acyl CoA dehydrogenases MCAD, VLCAD, and LCAD, and expression of enzymes involved in lipogenesis SCD and FAS. Collectively, these data indicate that the β-adrenergic receptors are dispensable for the adaptation of the liver to ketosis. The effect of KD consumption on browning of IWAT has not been previously examined. In cold exposed β3-adrenoreceptor knockout mice, white adipocytes do not increase expression of UCP1 and have reduced browning markers such as PGC-1α, CIDEA, and C/EBPβ [12]. By contrast, here we observed that β-less mice on KD are able to partially activate the thermogenic program in white adipose tissue, increasing expression of markers such as UCP1, Cox7a, C/EBPβ, and CPT1β while expression of other browning markers such as Cox8b and CIDEA is blunted. Together, these data show that (i) chronic consumption of KD requires intact SNS action and β-adrenergic receptors to induce certain browning markers but not the entire thermogenic program and (ii) KD induced IWAT browning is not sufficient for weight loss. Hepatic FGF21 has been established as an essential mediator of the physiologic adaptations to KD [2], and chronic consumption of the diet leads to marked induction of circulating FGF21 in both normal mice and obese mouse models [5,16]. Here we find that in β-less mice consuming KD, this effect is exaggerated with circulating FGF21 levels three fold higher than WT mice consuming KD (12,576 pg/ml in WT KD; 35,490 pg/ml in β-less KD). Despite having three-fold higher circulating FGF21 levels compared to WT mice on the diet, β-less mice on KD are unable to increase energy expenditure and activate BAT. This suggests that circulating FGF21 may require β-adrenergic receptors to activate BAT and induce weight loss on KD, indicative of a possible regulatory feedback loop from β-adrenergic receptors to FGF21 levels. We have previously observed that central or peripheral administration of FGF21 in β-less mice fails to induce IWAT browning [3]. By contrast, here we observe that chronic consumption of KD in β-less mice is able to partially activate the browning program in IWAT. We hypothesize that β-less mice on KD are able to brown IWAT through a cell autonomous mechanism involving a possible direct interaction between the very high circulating FGF21 levels and the KD itself. This is consistent with our previous demonstration that FGF21 can brown IWAT in a cell autonomous manner in WT mice [31], in addition to acting centrally to brown IWAT through SNS activation [3,7].