bims-ciryme 2025-01-19 papers

Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00484-4. [Epub ahead of print]

Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring.

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

Keywords: caloric restriction; circadian clock; circadian rhythm; developmental origins of health and disease; eating behavior; leptin; metabolism; obesity; pregnancy; time-restricted feeding

DOI: https://doi.org/10.1016/j.cmet.2024.12.002

Sci Transl Med. 2025 Jan 15. 17(781): eadr6459

Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis.

Baijie Xu, Katherine Lawler, Steven C Wyler, Li Li, Swati, Julia M Keogh, Xiameng Chen, Rong Wan, Amanda G Almeida, Susan Kirsch, Kathleen G Mountjoy, Joel K Elmquist, I Sadaf Farooqi, Chen Liu.

Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigated the transcriptional regulation of MC4R in the hypothalamus. In mice, we show that the homeodomain transcription factor Orthopedia (OTP) is enriched in MC4R neurons in the paraventricular nucleus (PVN) of the hypothalamus and directly regulates Mc4r transcription. Deletion of Otp in PVN neurons during development or adulthood reduced Mc4r expression, causing increased food intake and obesity. In humans, four of the five carriers of rare predicted functional OTP variants in UK Biobank had obesity. To explore a causal role for human OTP variants, we generated mice with a loss-of-function OTP mutation identified in a child with severe obesity. Heterozygous knock-in mice exhibited hyperphagia and obesity, reversed by treatment with an MC4R agonist. Our findings demonstrate that OTP regulates mammalian energy homeostasis and enable the diagnosis and treatment of individuals with obesity due to OTP deficiency.

DOI: https://doi.org/10.1126/scitranslmed.adr6459

Diabet Med. 2025 Jan 11. e15506

Protocol for a 1-year randomised, controlled, parallel group, open-label trial on the effects and feasibility of time-restricted eating in individuals with type 2 diabetes- The Restricted Eating Time in the Treatment of Type 2 Diabetes (RESET2) trial.

Anne-Ditte Termannsen, Annemarie Varming, Natasja Bjerre, Helena Z Wodschow, Gitte S Hansen, Nicole J Jensen, Frederik Persson, Jonatan I Bagger, Satchidananda Panda, Graham Finlayson, Bettina Ewers, Dorte L Hansen, Kirsten Nørgaard, Jørgen Rungby, Louise G Grunnet, Martin B Blond, Nana F Hempler, Kristine Færch, Jonas S Quist.

AIM: Time-restricted eating (TRE) limits the time for food intake to typically 6-10 h/day without other dietary restrictions. The aim of the RESET2 (the REStricted Eating Time in the treatment of type 2 diabetes) trial is to investigate the effects on glycaemic control (HbA1c) and the feasibility of a 1-year TRE intervention in individuals with overweight/obesity and type 2 diabetes. The aim of the present paper is to describe the protocol for the RESET2 trial.
METHODS: RESET2 is a randomised, controlled, parallel-group, open-label trial. One hundred and sixty individuals with type 2 diabetes (HbA1c >53 mmol/mol (>7.0%)), and Body Mass Index ≥25 kg/m2 will be randomised to standard care plus TRE, or to standard care and habitual living. Both the intervention and control group will follow standard diabetes care including regular clinical visits 3-4 times/year. The intervention is divided into two periods: (1) a 3-month TRE period with a fixed eating window with a self-selected timing to obtain data from the participants' experiences with TRE and (2) a 9-month individually adjusted TRE period. Participants in the TRE group will be instructed to reduce their eating window by a minimum of 3 h/day compared to the habitual eating window and with an eating window of 8-10 h/day. Test days will be scheduled at baseline, after 3 months and after 1 year. The primary outcome is HbA1c (evaluated 3 months and 1 year after randomisation) and secondary outcomes are body weight, fat mass, continuous glucose monitoring derived time-in-range and use of antidiabetic medicine (evaluated 1 year after randomisation). Additionally, we will conduct a process evaluation to assess whether the TRE intervention functioned as hypothesised.

Keywords: diabetes mellitus type 2; diet; fasting; obesity; overweight

DOI: https://doi.org/10.1111/dme.15506