bims-stacyt 2023-12-10 papers

Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00414-X. [Epub ahead of print]35(12): 2165-2182.e7

GDF15 is a major determinant of ketogenic diet-induced weight loss.

Jun Feng Lu, Meng Qing Zhu, Bo Xia, Na Na Zhang, Xiao Peng Liu, Huan Liu, Rui Xin Zhang, Jun Ying Xiao, Hui Yang, Ying Qi Zhang, Xiao Miao Li, Jiang Wei Wu.

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.

Keywords: GDF15; GFRAL; hepatic PPARγ; ketogenic diet; obesity

DOI: https://doi.org/10.1016/j.cmet.2023.11.003

Eur J Pharmacol. 2023 Dec 04. pii: S0014-2999(23)00762-8. [Epub ahead of print] 176248

Endocrine FGFs and their signaling in the brain: Relevance for energy homeostasis.

Lucas Zangerolamo, Marina Carvalho, Licio A Velloso, Helena C L Barbosa.

Since their discovery in 2000, there has been a continuous expansion of studies investigating the physiology, biochemistry, and pharmacology of endocrine fibroblast growth factors (FGFs). FGF19, FGF21, and FGF23 comprise a subfamily with attributes that distinguish them from typical FGFs, as they can act as hormones and are, therefore, referred to as endocrine FGFs. As they participate in a broad cross-organ endocrine signaling axis, endocrine FGFs are crucial lipidic, glycemic, and energetic metabolism regulators during energy availability fluctuations. They function as powerful metabolic signals in physiological responses induced by metabolic diseases, like type 2 diabetes and obesity. Pharmacologically, FGF19 and FGF21 cause body weight loss and ameliorate glucose homeostasis and energy expenditure in rodents and humans. In contrast, FGF23 expression in mice and humans has been linked with insulin resistance and obesity. Here, we discuss emerging concepts in endocrine FGF signaling in the brain and critically assess their putative role as therapeutic targets for treating metabolic disorders.

Keywords: Central nervous system; Energy metabolism; Fibroblast growth factor; Hypothalamus; Obesity; Sympathetic nervous system

DOI: https://doi.org/10.1016/j.ejphar.2023.176248

Biotechnol Appl Biochem. 2023 Dec 06.

Evaluation of the relationship of cytokines concentrations tumor necrosis factor-alpha, interleukin-6, and C-reactive protein in obese diabetics and obese non-diabetics: A comparative study.

Imad Jassim Mohammad, Soheila Kashanian, Ronak Rafipour, Husam Aljwaid, Sadegh Hashemi.

Obesity has been linked to a low-grade inflammatory process in the white adipose tissue. Our study aims to detect the relationship between cytokine levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) in obese diabetics, compared to obese non-diabetics, Iraqi individuals. Ninety Iraqi adults, 45 type 2 diabetic and 45 non-diabetic obese, were selected as controls. Serum levels of TNF-α, IL-6, CRP, homeostatic model assessment for homeostasis model assessment of insulin resistance (HOMA-IR), body fat, and body mass index (BMI) were measured. The concentration of TNF-α, IL-6, and CRP were significantly greater in the obese diabetics, compared to the obese non-diabetics. BMI was significantly positively correlated with the concentration of TNF-α, IL-6, and CRP in the two groups. At the same time, HOMA-IR was non-significantly positively associated with them in obese diabetics. In contrast, the correlation was significantly positive between HOMA-IR with TNF-a, IL-6, and CRP in the obese non-diabetics group. Obese diabetics have more inflammation than obese non-diabetics as evidenced by the former's higher levels of TNF-α and IL-6. Obesity-related imbalances disrupt metabolic processes and increase CRP, TNF-, and IL-6 levels. Therefore, IR is promoted by the increase of cytokines.

Keywords: CRP; IL-6; TNF-α; insulin resistance; obesity; type 2 diabetes

DOI: https://doi.org/10.1002/bab.2539