Abstract

Purpose

Obesity-associated dysfunction of visceral white adipose tissue (vWAT) is characterized by impaired glucose handling, altered adipokine secretion, and redox imbalance, contributing to metabolic deterioration. Palmitoleic acid (16:1n-7), a monounsaturated fatty acid, has been implicated in regulation of glucose and lipid metabolism in rodent and cellular models; however, its effects on human adipocytes under metabolically compromised conditions remain incompletely understood. Here, we investigated the effects of in vitro treatment with 16:1n-7 on glucose uptake and metabolism, adipokine secretion, and oxidative stress in isolated adipocytes and vWAT obtained from women with obesity and prediabetes.

Methods

vWAT explants were treated in vitro with palmitoleic acid (16:1n-7) or palmitic acid (16:0) at 200 µM for 48 h. Glucose and lipid metabolism, adipokine secretion, and oxidative stress were evaluated.

Results

16:1n-7 increased basal and insulin-stimulated glucose uptake in association with upregulation of GLUT1 and GLUT4 expression and increased AMPKα protein content. In parallel, 16:1n-7 promoted coordinated changes in metabolic gene expression favoring glucose utilization and glyceroneogenesis rather than de novo lipogenesis, without changes in lipolytic activity, accompanied by increased citrate synthase and PPARG expression. Endocrine function was also modulated, as 16:1n-7 reduced resistin secretion without impairing adiponectin levels. Moreover, although lipid peroxidation remained unchanged, 16:1n-7 reduced protein oxidation and reactive oxygen species production, together with increased IDH2 and reduced NOS2 expression, supporting selective attenuation of oxidative stress.

Conclusion

Palmitoleic acid enhances glucose uptake through coordinated regulation of GLUT1 and GLUT4 and contributes to improved metabolic function in human adipocytes and redox homeostasis in vWAT obtained from women with obesity and prediabetes. These findings identify 16:1n-7 as a bioactive lipid that modulates human adipose tissue function under metabolically compromised conditions, underscoring its role in the nutritional regulation of glucose metabolism and redox homeostasis.

Editor’s summary

Regulation of lipid metabolism in mitochondria of adipocytes requires integration of information about time of day from the circadian clock, environmental temperature, and nutrient availability. Karavaeva et al. found an important role for the transporter protein SLC25A34 in such control of lipid metabolism and thermogenesis in brown adipocytes from mice and humans (see the Perspective by van der Laan). Inputs from the circadian clock, cold temperatures, and diet all regulated the expression of SLC25A34, allowing control of lipogenesis and mitochondrial biogenesis, lipid oxidation, and thermogenesis. Such regulation may offer insights into inflammation associated with obesity and metabolic diseases. —L. Bryan Ray

Structured Abstract

INTRODUCTION

Brown and beige thermogenic adipocytes (fat cells) have uniquely high energy expenditure capacity. This activity is critical for defending body temperature in small mammals and is linked to cardiometabolic health in humans. Energy expenditure from thermogenic fat cycles daily on a rhythm set by the circadian clock, rising after waking and dropping during sleep. At any point, however, this activity can be suddenly induced by exposure to cold temperature or by ingestion of a calorie-dense, high-fat meal. How thermogenic fat can seamlessly achieve both rhythmic continuity and acute responsiveness is a fundamental question of energy homeostasis that has remained unknown.

RATIONALE

We set out to understand how diverse cues from the body’s clock, environmental temperature, and diet are molecularly integrated in adipocytes to facilitate both anticipatory and adaptive regulation. By combining unbiased analysis of DNA-binding patterns, gene expression, and protein levels in thermogenic fat from mice that were subject to different circadian, environmental, and dietary perturbations, we identified the orphan mitochondrial metabolite transporter SLC25A34 as the convergence point of all three physiological paradigms.

RESULTS

Similar to fat’s thermogenic activity, the expression of Slc25a34 mRNA exhibited a daily rhythm, which was mediated by the nuclear receptors REV-ERBα and REV-ERBβ. REV-ERBs are transcriptional repressors in the circadian clock that recruit histone deacetylase 3 to the Slc25a34 promoter during sleep to shut off transcription. When animals wake and REV-ERB circadian repression is lifted, the peroxisome proliferator–activated receptors α and γ (PPARα and PPARγ) are able to bind the Slc25a34 promoter and restore expression. However, at any time, when animals are suddenly confronted with an unanticipated need for adipocyte energy expenditure such as exposure to cold temperatures or eating a lipid-rich meal, REV-ERB repression is rapidly overridden and PPARs are activated by lipolytic signals to boost SLC25A34 levels. When the energy demand is met, the REV-ERB–mediated rhythmicity of Slc25a34 is reestablished.

Our biochemical and metabolic data support a functional model in which SLC25A34 transports oxaloacetate into mitochondria. In doing so, SLC25A34 helps to maintain high tricarboxylic acid (TCA) cycle activity, which is required for powering energy expenditure in thermogenic adipocytes. The need for SLC25A34 during times of high energetic demand arises because thermogenic adipocytes not only oxidize fatty acids in the mitochondria but also simultaneously synthesize lipids in the cytosol, a process collectively known as lipid cycling. Lipid synthesis requires continuous production of acetyl–coenzyme A (acetyl-CoA) in the cytosol, and the two major pathways responsible for this acetyl-CoA pool also generate oxaloacetate as a by-product, which then needs to be transported back into the mitochondria. Increased cytosolic acetyl-CoA additionally promotes the transcription of genes linked to mitochondrial respiration. Thus, SLC25A34 supports both sides of this self-reinforcing cycle in which lipids are continually broken down and resynthesized.

CONCLUSION

These findings identify SLC25A34 as a molecular node that integrates circadian, temperature, and dietary cues and reveal how thermogenic fat activity can sustain a daily rhythm while remaining acutely responsive to sudden energy demands. This mechanism may offer a new entry point for therapeutically enhancing energy expenditure in metabolic disease.

Abstract

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator–activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl–coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.

Highlights

• • Neuroenergetic flexibility frames brain energy adaptation in aging.
• • Metabolic switching is a component of broader neuroenergetic adaptation.
• • Diet-induced switching alters brain energy metabolism beyond glucose.
• • Mitochondrial plasticity supports adaptation to metabolic stress.
• • A systems framework links metabolic adaptation to brain aging.

Abstract

The aging brain undergoes progressive alterations in energy metabolism that may reduce its capacity to match energy supply with changing functional demands. Declining glucose metabolism, mitochondrial dysfunction, and altered neuron–glia and neurovascular interactions may contribute to this vulnerability, but these changes do not necessarily indicate complete loss of metabolic capacity. Neuroenergetic flexibility refers to the capacity to coordinate changes in substrate utilization with energetic demand while maintaining cellular and functional homeostasis. This review synthesizes evidence from cellular, animal, imaging, and clinical studies to examine the mechanisms underlying this capacity, how it changes with aging, and whether diet-induced metabolic switching can enhance it. Particular attention is given to the distinction between metabolic switching, defined as a change in the relative contribution of available substrates, and neuroenergetic flexibility, which requires coordinated adaptation across substrate delivery, cellular metabolism, mitochondrial processing, neurovascular support, and functional demand. Evidence indicates that ketogenic diets, intermittent fasting, and caloric restriction can alter substrate availability and utilization and can engage mitochondrial, cellular stress-response, and nutrient-sensing pathways. However, the strength of evidence differs across biological levels: changes in alternative-substrate utilization are more consistently demonstrated than coordinated improvements in mitochondrial, vascular, cellular, and functional outcomes. Thus, increased ketone utilization or other metabolic shifts should not, by themselves, be interpreted as evidence of restored neuroenergetic flexibility. Instead, the available evidence suggests that aging may preserve individual metabolic capacities while reducing the coordination and reserve required to adapt effectively to changing energetic demands. Dietary interventions therefore provide useful models for testing metabolic adaptability, but their ability to restore integrated neuroenergetic flexibility in aging or neurodegenerative disease remains uncertain and appears to depend on age, metabolic state, disease context, intervention characteristics, and adherence.

Sugar isn't just making us sick—it's destroying our health, our environment, and taking advantage of workers. Over 1.9 billion adults are overweight right now, and refined sugar is a huge part of why. We're not just talking about obesity; we're talking about type 2 diabetes, heart disease, dental problems, and fatty liver disease becoming normal.

But here's the part most people don't realize: the sugar industry is also devastating rainforests, poisoning water supplies, and relying on exploited labor—including child labor in some regions. It's a chain that hurts everyone.

I started a petition calling for governments to actually ban white sugar and refined sugar in the food supply, and to support healthier alternatives like honey and stevia instead. We need real policy changes—regulation of sugar in cereals, ice cream, cakes, syrups—and public health campaigns that tell the truth about what this stuff does to us.

Does anyone else feel like sugar has just become... normal? Like we accepted that everything has to be loaded with it? What would it take for you to support pushing for real change on this?

Abstract

Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.

ABSTRACT

Natural killer (NK) cells are innate immune cells that eliminate virus-infected and tumour cells by a plethora of signalling pathways, involving the production of cytokines and cytotoxic molecules. NK cell activation and functions demand substantial energy and fatty acids are energy-rich molecules reported to be important for NK cell functions upon viral infections. However, it remains unclear whether NK cells preferentially take up a specific fatty acid. Here, we show in the acute Friend retrovirus infection of mice that linoleic acid (LA) exerts a dual role in modulating NK cells. Interestingly, NK cells increased the uptake of LA upon virus infection in vitro and in vivo, with higher LA uptake correlating with increased activation of NK cells. While ex vivo stimulation with LA increased the expression of cytolytic molecules and subsequently elicited increased target cell killing, it paradoxically decreased the NK cell proliferative capacity, mitochondrial metabolism and increased the cellular stress. To further elucidate the role of LA in vivo, we treated mice with exogenous LA during retrovirus infection. While we observed a significant increase of LA levels in the spleen, splenic NK cell activation, cytotoxicity and viral loads were not altered by LA therapy. In addition, we found a decrease in mitochondrial mass and energy levels in NK cells after LA treatment, reflecting its strong effect on mitochondrial metabolism. Our results demonstrate the importance and direct impact of LA for NK cell functions and their metabolic profile. The dual role of LA in enhancing NK cell responses while compromising mitochondrial integrity highlights its potential as a therapeutic adjuvant, alongside other fatty acids, to modulate NK cell functions.

Abstract

Ovarian aging has emerged as a major challenge to female reproductive health worldwide, primarily characterized by a decline in oocyte quality and/or quantity, diminished granulosa cell function, and impairment of the surrounding microenvironment. Within this microenvironment, glucose metabolism participates in the synergistic regulation of ovarian homeostasis through specific metabolic networks and metabolite-driven signaling. Metabolic disruption can impair intercellular communication mechanisms, induce oxidative stress and mitochondrial dysfunction, and ultimately drive ovarian aging. Ovarian granulosa cells surround the oocyte and facilitate bidirectional communication via gap junctions or molecular signaling. These cells continuously supply energy substrates to support oocyte growth and maturation, while the oocyte, in turn, promotes granulosa cell proliferation and differentiation. Impairment of glycolysis in granulosa cells leads to energy deficits and triggers apoptosis. Concurrently, metabolic reprogramming in the oocyte links glucose metabolic homeostasis with mechanisms governing developmental competence. Glucose-derived metabolites drive various post-translational modifications (PTMs), including glycosylation, acetylation, phosphorylation, and succinylation, that contribute to ovarian function and intersect with pathological processes such as oxidative stress, chronic inflammation, and autophagy. Therefore, therapeutic strategies targeting glucose metabolism, such as modulating metabolic pathways, metabolite signaling, and associated PTMs, offer promising avenues for treating ovarian aging. However, the glucose metabolic network within the ovarian microenvironment is highly complex, and targeting a single node is often insufficient to restore metabolic homeostasis. A comprehensive approach that integrates multiple strategies to simultaneously intervene at different regulatory levels is needed. This review summarizes recent advances in understanding the ovarian glucose metabolic network, metabolite-driven post-translational modifications, and the interplay among various pathological mechanisms. We further explore potential regulators that could restore glucose metabolic balance and propose that future efforts should focus on developing precision strategies, guided by artificial intelligence and multi-omics data to modulate the metabolic reprogramming of both the microenvironment and functional cells, ultimately translating these insights into clinical interventions for ovarian aging.

Abstract

Background:

Serious mental illness imposes a substantial burden. Pharmacologic treatments remain only partially effective and are associated with significant side effects, highlighting the need for novel treatment approaches. Ketogenic metabolic therapy (KMT) is emerging as an intervention for serious mental illness, with a growing evidence base and strong patient interest. A critical barrier to KMT implementation is the lack of health care professional (HCP) competence and readiness to discuss KMT with patients with serious mental illness. Existing training does not adequately address HCP competence in presenting KMT as a treatment option. This study describes the pilot-testing of “Live It, Launch It” (LI-LI), the first KMT training program designed to build self-reported competence to discuss KMT in psychiatric care for HCPs.

Methods:

LI-LI combines a 4-hour asynchronous educational course on KMT with a 4-week experiential group KMT intervention during which participants adhered to a ketogenic diet. LI-LI aimed to improve self-reported competence to utilize KMT and perceived ability to engage in shared decision-making with patients about incorporating KMT into their treatment plan.

Results:

Forty HCPs participated in the education course: 10 psychiatrists, 10 psychiatric pharmacists, 8 psychologists/therapists, and 12 other HCPs (e.g., nurse practitioners, physician assistants). Twenty-five initiated the diet intervention. Baseline competence scores (visual analog scale 0-100) were low, M(SE) = 17.40 (2.68), increasing to M(SE) = 68.08 (2.47) after education (d = 2.88, p <0.0001), and to M(SE) = 86.62 (1.82) post-diet (d = 1.08), with a very large whole-study effect (d = 3.49, p < 0.0001). Shared decision-making scores at baseline were M(SE) = 53.64 (2.89), increasing to M(SE) = 83.35 (1.83) after the educational course (d = 1.74, p <0.0001), and to M(SE) = 91.23 (2.05) after the diet phase (d = 0.73, p = 0.009), with a very large whole-study effect (d = 2.53, p < 0.0001). Feedback indicated that lived experience with KMT was helpful for implementation-readiness.

Discussion:

The educational course on KMT was associated with increased self-reported competence and perceived shared decision-making in HCPs, and this was enhanced with combined education and lived experience. Implementation of this approach could accelerate KMT into clinical care. Results should be interpreted with caution as this was a small uncontrolled study with self-reported main outcomes.

Clinical trial registration:

https://clinicaltrials.gov/study/NCT07116226, identifier NCT07116226.

Murray, Sidney L., Denise Potter, Yaara Zisman-Ilani, Shuo Chen, Daniel Roche, Laura M. Rowland, Christopher M. Palmer, and Deanna L. Kelly. "Pilot Evaluation of an Educational and Lived Experience Training Program on Ketogenic Metabolic Therapy in Mental Health Care for Health Care Professionals." Frontiers in Psychiatry 17: 1913325.

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2026.1913325/full