Ricardo Orozco-Solis

This study explores the role of human visceral white adipocytes (hv-WAD) in latent tuberculosis infection (LTBI). While granulomas and macrophages are traditionally viewed as central to TB latency, emerging evidence highlights adipocytes as significant non-canonical host cells that may facilitate bacterial persistence by providing a protective niche. Unlike the immune-driven environment within granulomas, adipocytes can shield Mycobacterium tuberculosis (Mtb) from immune surveillance, promoting survival. In vitro experiments showed that Mtb invades approximately 39% of hv-WAD within 48–72 h post-infection (hpi). Both avirulent H37Ra and virulent H37Rv Mtb strains, when infecting adipocytes, expressed RNA for key virulence factors (19 kDa, 30 kDa, Ag85b, 5KST, CFP10, and ESAT6) and dormancy-associated genes (Icl1, LipY, WhiB3, SodA, and Tgs1) at 72 hpi. Infection stimulated the production of inflammatory cytokines, notably leading to a fivefold increase in TNF-α with H37Rv (p < 0.01). Additionally, we detected Mtb RNA transcripts (IS6110, 5KST, 30 kDa, CFP10, Ag85) in 68% of biopsies from TB asymptomatic patients. The transcripts suggest a metabolically heterogeneous state of mycobacteria. These findings position visceral fat as a potential reservoir for Mtb in latent TB infection and underscore the development of novel diagnostic strategies targeting adipose tissue.

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues are known for their remarkable catabolic capacity, and their ability to diminish blood glucose plasma concentration. Beige adipose tissue can be differentiated from adipose-derived stem cells or through transdifferentiation from white adipocytes. However, the impact of T2D progression on beige adipocytes' functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, obese, prediabetic obese, and obese subjects diagnosed with T2D, reveals a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX is a potential transcription factor that links inflammation with the circadian clock and thermogenesis during the progression of T2D. This study unveils an unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during the progression of T2D. These findings could open new research venues for developing chrono-pharmaceutical strategies to treat and prevent T2D.

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues, known for their remarkable catabolic capacity, can lower blood glucose levels. Beige adipose tissue can be differentiated from adipose stem cells or through transdifferentiation from white adipose tissue. However, the impact of T2D progression on beige adipocyte functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, healthy obese, prediabetic obese, and obese T2D patients revealed a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX was identified as a potential transcription factor linking inflammation with the circadian clock and thermogenesis during T2D progression. This study unveils a previously unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during T2D progression. These findings could open new research avenues for developing chronopharmaceutical strategies to treat and prevent T2D.

Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions.

The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD⁺. Increasing NAD⁺ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD⁺ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD⁺ treatment for diet-induced metabolic disease in mice. Increasing NAD⁺ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD⁺ immediately before the rest phase selectively compromised these responses. Remarkably, timed NAD⁺ adjusted circadian oscillations of the liver clock until completely inverting its oscillatory phase when increased just before the rest period, resulting in misaligned molecular and behavioral rhythms in male and female mice. Our findings unveil the time-of-day dependence of NAD⁺-based therapies and support a chronobiology-based approach.

Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core‐clock gene Bmal1 within Gfap‐expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo‐caloric diet, under high‐fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER‐stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.

Adipocytes are the main cell type in adipose tissue, which is a critical regulator of metabolism, highly specialized in storing energy as fat. Adipocytes differentiate from multipotent mesenchymal stromal cells (hMSCs) through adipogenesis, a tightly controlled differentiation process involving close interplay between metabolic transitions and sequential programs of gene expression. However, the specific gears driving this interplay remain largely obscure. Additionally, the metabolite nicotinamide adenine dinucleotide (NAD+) is becoming increasingly recognized as a regulator of lipid metabolism, and a promising therapeutic target for dyslipidemia and obesity. Here, we explored how NAD+ bioavailability controls adipogenic differentiation from hMSC. We found a previously unappreciated repressive role for NAD+ on adipocyte commitment, while a functional NAD+-dependent deacetylase SIRT1 appeared crucial for terminal differentiation of pre-adipocytes. Repressing NAD+ biosynthesis during adipogenesis promoted the adipogenic transcriptional program, while two-photon microscopy and extracellular flux analyses suggest that SIRT1 activity mostly relies on the metabolic switch. Interestingly, SIRT1 controls subcellular compartmentalization of redox metabolism during adipogenesis.

A growing number of epidemiological and experimental studies has established that circadian disruption is strongly associated with psychiatric disorders, including major depressive disorder (MDD). This association is becoming increasingly relevant considering that modern lifestyles, social zeitgebers (time cues) and genetic variants contribute to disrupting circadian rhythms that may lead to psychiatric disorders. Circadian abnormalities associated with MDD include dysregulated rhythms of sleep, temperature, hormonal secretions, and mood which are modulated by the molecular clock. Rapid-acting antidepressants such as subanesthetic ketamine and sleep deprivation therapy can improve symptoms within 24 h in a subset of depressed patients, in striking contrast to conventional treatments, which generally require weeks for a full clinical response. Importantly, animal data show that sleep deprivation and ketamine have overlapping effects on clock gene expression. Furthermore, emerging data implicate the circadian system as a critical component involved in rapid antidepressant responses via several intracellular signaling pathways such as GSK3β, mTOR, MAPK, and NOTCH to initiate synaptic plasticity. Future research on the relationship between depression and the circadian clock may contribute to the development of novel therapeutic strategies for depression-like symptoms. In this review we summarize recent evidence describing: (1) how the circadian clock is implicated in depression, (2) how clock genes may contribute to fast-acting antidepressants, and (3) the mechanistic links between the clock genes driving circadian rhythms and neuroplasticity.

The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. A specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. Hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. Interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. This clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. Immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. Hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. Certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.