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. 2024 Mar 20;16(6):4980-4999.
doi: 10.18632/aging.205673. Epub 2024 Mar 20.

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction

Alcir L Dafre  1   2 , Saadia Zahid  1   3 , Jessica Jorge Probst  2 , Antonio Currais  1 , Jingting Yu  4 , David Schubert  1 , Pamela Maher  1
Affiliations

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction

Alcir L Dafre et al. Aging (Albany NY). .

Abstract

Background: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice.

Methods: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism.

Results: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121.

Conclusions: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.

Keywords: diabetes; geroneuroprotection; ketogenic diet; metabolic disorders; obesity.

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Conflict of interest statement

CONFLICTS OF INTEREST: PM is on the Scientific Advisory Boards of NOVOS and Dong-A ST. The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Nutritional, body mass, locomotor activity, and metabolic activity of mice fed a control diet or a diet containing the geroneuroprotective drug candidate CMS121 for 6 months. Beginning at the 5th week after birth, mice were either kept on the control diet (CTL) or put on a diet containing CMS121 ad libitum. Cumulative food intake (A) and body weight (B). Food intake per animal was based on the average food consumption in cages holding 3 mice allocated among a total of 4 cages, and the body weight of 12 mice was followed. Differences between linear regression slopes of CTL and CMS121-treated mice were analyzed and the p-values are shown. Initial and final body weights are presented (C). During the 13th week of treatment body mass (n = 12) indexes were obtained: lean mass (D), and fat mass (E). Metabolic activity (F–H) was evaluated at the 15th week of treatment for oxygen consumption (VO2) (F); carbon dioxide production (VCO2) (G); respiratory exchange ratio (RER) (H), and ambulatory activity (I); Data are presented as mean ± SD (n = 4). Bold underlined p-values indicate statistical differences.
Figure 2
Figure 2
Glucose status in mice treated with CMS121 for 6 months. The glucose tolerance test (GTT, n = 4–5) was performed at the 6th month of treatment (A). The area under the curve (AUC) is presented in (B). Glucose was evaluated by caudal vein puncture after the 5th month of treatment in fed mice (C) (n = 8). At the end of the study, blood was collected for the measurement of fasting glucose (D) (n = 4), glycated hemoglobin (E) (HbA1c; n = 8–9), and insulin levels (F) (n = 6–7). Data are presented as mean ± SD, except for GTT (mean ± SEM). Bold underlined p-values indicate statistical differences.
Figure 3
Figure 3
Blood and liver lipids of mice fed control diet or a diet containing CMS121 for 6 months. Plasma (A–C) and liver (D–F) were evaluated for free fatty acids (FFA (A, D)), triglycerides (B, E), and cholesterol (C, F) at the end of the experiment. Data are presented as mean ± SD (n = 7–8). Bold underlined p-values indicate statistical differences.
Figure 4
Figure 4
Adipose tissue metabolic markers were evaluated in mice fed with CMS121 for 6 months. Representative slot blot (A) or Western blot (B) images of mitochondrial fractions from adipose tissue are presented. Quantitative results (C–K) of proteins related to mitochondrial metabolism, such as transcription factors Nrf1 (C) and TFAM (D), markers of lipid (p-ACC1, (E)) and glucose (GLUT4, (F)) metabolism, and markers of mitochondrial complex I ((G); NDUFB8), complex II ((H); SDHB), complex III ((I); UQCRC2), and complex V ((J); ATP5A) are presented, as well as the levels of the outer membrane translocase TOM20 (K). Data are presented as mean + SD (n = 6–8). Bold underlined values of p indicate statistical differences.
Figure 5
Figure 5
Liver protein markers were evaluated in mice fed with CMS121 for 6 months. Representative blot images (A), and the corresponding quantification (B–R) of metabolism markers in the hepatic tissue: FASN (B), PEPCK (C), p-LDH-A (D), PFKFB3 (E), TXNIP (F), MLYCD (G), malonylation of proteins at lysine residues (MAL-K, (H)), FH (I), Nox4 (J), caspase 1 (K), caspase 3 (L), and markers of mitochondrial complex I ((M); NDUFB8), complex II ((N); SDHB), complex III ((O); UQCRC2), and complex V ((P); ATP5A), as well as the voltage dependent anion channel VDAC (Q), and the outer membrane translocase TOM20 (R). Liver cytosolic fractions were used for blotting, except for the mitochondrial markers (M–R), FH (I), and NOX4 (J) that used mitochondrial fractions. Data are presented as mean ± SD (N = 6–8). Bold underlined p-values indicate statistical differences.
Figure 6
Figure 6
Effect of the CMS121 diet on plasma metabolites. Differentially expressed metabolites are presented as (A) heat map; (B) volcano plot; (C) table presenting the top ten upregulated or downregulated metabolites, and metabolites related to lipids (D) or amino acids (E). Only sub-pathways with 3 or more differentially expressed metabolites are presented in (D and E), and represent the average ± SD. Abbreviations are: BCAA – branched chain amino acids; Butyrate-X – indicates 4 carbon metabolites related to β-hydroxybutyrate; S/M Acylcarn – small or medium acylcarnitine metabolites; L/Acyl FA – long saturated/monoinsaturated free or acyl fatty acids; L-Poly FA – long polyunsaturated free or acyl-fatty acids. *Indicates compounds that have not been confirmed based on a standard, but mass spectral data were appropriate to reveal their identity.
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