Body Fat's Daily Rhythm Problems Beyond Weight Linked to Heart and Metabolic Health Risks

BMI remains the most widely used criterion for defining obesity, yet it provides only a static, cross-sectional estimate of body size and fails to capture the marked biological heterogeneity observed among individuals with similar BMI values. In particular, BMI does not distinguish fat mass from lean mass or account for inter-individual differences in adipose tissue distribution, limitations that substantially weaken its ability to estimate cardiometabolic risk at the individual level. These shortcomings are reflected in the recognition of distinct obesity phenotypes, including metabolically healthy obesity (MHO) and metabolically unhealthy normal weight (MUNW), illustrating that BMI-based categories often fail to align with underlying metabolic status [11].

The concept of MHO emerged from observations that a subset of individuals with obesity lack overt cardiometabolic abnormalities at a given time point. Although definitions vary, MHO is generally characterized by the absence of major metabolic disturbances such as dyslipidemia, insulin resistance, hyperglycemia, and hypertension. However, the absence of consensus criteria has resulted in wide variability in reported prevalence and limited comparability across studies. As a result, MHO should not be interpreted as a benign or stable condition, as obesity is associated with adverse health outcomes that extend beyond conventional cardiometabolic risk factors [11,12].

A critical limitation of BMI-based classification is its inability to capture the dynamic nature of metabolic health over time. Longitudinal studies indicate that MHO frequently represents a transient phenotype rather than a stable state [13]. Evidence also shows that a substantial proportion of individuals initially classified as MHO develop metabolic abnormalities during follow-up, underscoring that cardiometabolic risk can evolve independently of BMI-defined obesity [14]. Similarly, a three-year follow-up study in a Mexican cohort reported that approximately one-third of participants transitioned between metabolic phenotypes, with the highest rate of change observed among those initially classified as MHO [15]. Thus, it is safe to assume that metabolic health exists along a continuum and can shift over clinically relevant timeframes—changes that static anthropometric measures such as BMI cannot anticipate.

The existence of MHO and MUNW, together with the frequent instability of metabolic phenotypes over time, shows BMI’s limitation as a static descriptor of a biologically and clinically dynamic condition. This temporal instability provides a compelling rationale for moving beyond BMI-only assessments when investigating mechanisms and modifiers of cardiometabolic risk, including the role of time-dependent regulatory processes such as circadian organization of adipose tissue function, discussed in subsequent sections.

Recognition of BMI’s limitations has prompted increasing use of imaging-based approaches to directly quantify adipose tissue distribution. Modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and echocardiography allow precise assessment of visceral and ectopic fat depots, providing substantially greater anatomical resolution than anthropometric indices alone. Imaging-derived measures of visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) have been shown to improve cardiometabolic risk stratification compared with BMI, particularly by identifying high-risk phenotypes among both obese and normal-weight individuals [11].

Among ectopic depots, EAT has received particular attention because of its close anatomical relationship with the myocardium and coronary vasculature. Translational and clinical studies indicate that EAT expansion is associated with local inflammation, myocardial fibrosis, and impaired diastolic function, especially in individuals with type 2 diabetes [16]. Imaging-based quantification of EAT therefore captures regionally relevant adiposity with direct pathophysiological implications for cardiovascular disease, beyond what can be inferred from generalized measures of obesity.

Prospective population data further support the clinical relevance of imaging-defined adiposity. In the Framingham Heart Study, directly measured VAT was independently associated with incident cardiovascular disease and cancer after adjustment for BMI and traditional risk factors, whereas subcutaneous adipose tissue was not [17].

Despite these advances, imaging-based metrics remain inherently structural. While they quantify adipose tissue volume or thickness with high precision, they provide limited insight into adipose tissue function, inflammatory activity, metabolic flexibility, or temporal organization [11,16,17]. Consequently, although imaging refines risk stratification beyond BMI, it remains insufficient to explain phenotype instability or disease progression over time. Thus, the need to integrate functional and temporal frameworks, particularly the circadian regulation of adipose tissue biology, appears.

Metabolic homeostasis is regulated by a hierarchical circadian system composed of a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus and a network of peripheral clocks distributed across metabolic tissues. This system provides temporal structure to physiology, allowing metabolic processes to anticipate daily cycles of activity, feeding, and rest, thereby supporting efficient energy utilization and cardiometabolic function. The SCN functions as the principal timekeeper by aligning internal rhythms with the external light–dark cycle. Photonic signals detected by intrinsically photosensitive retinal ganglion cells are transmitted directly to the SCN, constituting the dominant entrainment signal for central circadian timing [18,19]. Beyond serving as a general synchronizing cue, light exposure exerts time-of-day-dependent effects on circadian alignment with important metabolic implications. Environmental light is the primary zeitgeber responsible for daily resetting of the central pacemaker, and inappropriate timing or intensity of light exposure can destabilize this process, promoting circadian misalignment between central and peripheral clocks. Experimental and translational studies indicate that such misalignment alters the temporal coordination of glucose regulation, insulin sensitivity, and energy metabolism, independent of sleep duration or caloric intake [6]. In humans, exposure to light during the biological evening or night is increasingly recognized as a contributor to chronodisruption, with downstream associations with obesity and metabolic dysfunction, consistent with impaired circadian regulation of adipose and other metabolic tissues [5,6]. These observations are in accordance with the view that light signaling represents an upstream regulator of metabolic rhythmicity rather than a secondary behavioral confounder [5,6,9].

The metabolic consequences of light exposure depend not only on its presence but also on its circadian timing. Light exposure during the biological evening or night induces phase delays of central circadian signals, including suppression and temporal displacement of melatonin secretion, thereby shifting internal biological timing relative to behavioral cycles [20]. This phase delay coincides with a circadian window characterized by reduced glucose tolerance, diminished insulin sensitivity, and altered lipid handling, increasing susceptibility to metabolic dysfunction when nutrient intake occurs at inappropriate circadian phases. Human experimental studies demonstrate that evening or nocturnal light exposure perturbs glucose and lipid regulation in a manner consistent with circadian misalignment, even in the absence of major changes in sleep duration or total caloric intake, supporting a mechanistic role for light-driven circadian disruption rather than purely behavioral mediation [20,21].

Consistent with these timing-dependent effects, alterations in the timing and intensity of light exposure are increasingly recognized as contributors to metabolic dysregulation through their effects on circadian alignment. Exposure to light at inappropriate circadian phases, particularly during the biological evening or night, can perturb glucose and lipid regulation in a manner consistent with circadian misalignment. These effects appear to depend more strongly on the timing and amplitude of light exposure than on photoperiod per se, reinforcing the importance of circadian phase–specific signaling. Such metabolic associations are observed even in the absence of major changes in sleep duration, supporting a mechanistic role for circadian disruption rather than purely behavioral mediation [5,6]. Once synchronized, the SCN coordinates peripheral clocks through integrated neural, endocrine, and physiological pathways, including rhythmic autonomic nervous system output, oscillations in body temperature, and hormonal signals such as glucocorticoids and melatonin. Through these outputs, temporal information is conveyed to peripheral organs [18,19,22]. Because peripheral metabolic tissues are also highly responsive to non-photic cues (particularly feeding–fasting cycles), mistimed food intake occurring in the context of delayed light-entrained central rhythms can partially uncouple peripheral clocks from SCN control. This central–peripheral desynchrony provides a mechanistic framework linking light-driven circadian misalignment to tissue-specific metabolic dysfunction, particularly within adipose and hepatic systems [20].

The hierarchical organization of central and peripheral circadian clocks, along with the major entrainment pathways relevant to metabolic regulation, is illustrated in Figure 1.

Peripheral circadian clocks are expressed in virtually all metabolic tissues, including liver, skeletal muscle, pancreas, cardiovascular tissues, and adipose depots, where they regulate local metabolic programs in a tissue-specific manner [22]. Although normally synchronized by the SCN, peripheral clocks retain sensitivity to non-photic zeitgebers, most notably feeding–fasting cycles and physical activity [18,19]. Under certain behavioral conditions, meal timing can selectively reset peripheral metabolic rhythms without fully realigning central circadian markers, resulting in partial dissociation between central and peripheral clocks [19].

Alignment between central and peripheral circadian systems is a key determinant of cardiometabolic health. Circadian misalignment, arising from shift work, irregular sleep timing, late chronotype (defined as a habitual preference for later circadian phase and sleep–wake timing), social jet lag, or mistimed food intake, has been consistently associated with increased risk of obesity, insulin resistance, dyslipidemia, hypertension, inflammation, and cardiovascular disease, independent of sleep duration and other lifestyle factors [18,19]. Chronotype represents a dynamic phenotype influenced by age, environmental light exposure, and seasonal factors, and should be distinguished from the intrinsic circadian period, which remains relatively stable across the lifespan. These associations support the view that circadian organization represents an independent dimension of metabolic regulation rather than a secondary consequence of altered behavior or adiposity.

Among non-photic cues, feeding–fasting cycles serve as particularly potent synchronizers of peripheral metabolic clocks. Experimental and translational studies demonstrate that the timing of food intake strongly shapes rhythmic metabolic function across organs, in some cases independently of total caloric intake or macronutrient composition. Time-restricted eating, which consolidates daily caloric intake within a consistent 8–12 h window, reinforces rhythmic nutrient sensing and promotes coordinated oscillations in glucose and lipid metabolism without requiring caloric restriction [23,24].

Human studies further illustrate the physiological relevance of circadian timing of food intake. Eating later relative to endogenous circadian phase, rather than clock time, is associated with increased body fat and higher BMI, independent of energy intake, diet composition, physical activity, or sleep duration [25]. Such observations suggest that misalignment between feeding behavior and internal circadian timing favors metabolic inefficiency and energy storage.

In addition to the SCN, other hypothalamic nuclei involved in energy balance, glucose regulation, and autonomic control display intrinsic rhythmicity and integrate signals from both central and peripheral clocks. Through coordinated neural and humoral outputs, this distributed circadian network regulates glucose production, insulin secretion, lipid mobilization, and thermogenesis across the daily cycle [24,26].

Disruption of this temporal architecture alters communication between tissues and regulatory pathways, creating a metabolic environment prone to dysfunction even in the absence of overt changes in body mass. Within this framework, adipose tissue represents a particularly sensitive target of circadian perturbation, providing a mechanistic link between chronodisruption and cardiometabolic disease.

Adipose tissue functions as an autonomous peripheral circadian organ that integrates systemic timing cues with local endocrine, metabolic, and immune outputs. Experimental and translational studies show that both white and brown adipose depots exhibit intrinsic circadian rhythmicity, with coordinated oscillations that persist independently of the central clock while remaining highly responsive to feeding–fasting cycles and hormonal signals [10,27]. This dual autonomy and sensitivity position adipose tissue as a critical interface between circadian organization and whole-body metabolic homeostasis.

This temporal coordination is driven by the core molecular circadian clock, composed of transcriptional feedback loops involving circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period circadian protein (PER), cryptochrome (CRY), and nuclear receptor subfamily 1 group D member 1 (REV-ERBα) (Figure 2).

From an endocrine standpoint, adipose tissue displays marked daily variation in the secretion of adipokines and inflammatory mediators. Circulating levels of leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α, and interleukin-6 follow circadian patterns that mirror rhythmic activity within adipose depots [27]. These oscillations coincide with daily fluctuations in appetite regulation, insulin sensitivity, vascular tone, and thrombotic balance. When adipose circadian timing is disrupted, adipokine release becomes blunted or mistimed, favoring metabolic dysregulation and the development of low-grade inflammation.

At the metabolic level, adipose tissue clocks coordinate lipid storage and mobilization across the day–night cycle. Circadian regulation of lipolysis, fatty acid trafficking, and insulin responsiveness allows temporal partitioning between energy storage during feeding periods and substrate release during fasting states [24]. Disruption of this temporal organization, such as through irregular feeding schedules or shift work, impairs glucose tolerance, promotes ectopic lipid deposition, and exacerbates insulin resistance, even in the absence of significant changes in total caloric intake.

Adipose tissue appears particularly vulnerable to chronodisruption because of its strong dependence on behavioral and nutritional zeitgebers. Both experimental models and human studies indicate that mistimed feeding induces phase shifts and desynchronization of adipose circadian outputs relative to central and hepatic clocks [24,27]. In individuals with obesity, visceral adipose tissue shows altered temporal organization that correlates with components of the metabolic syndrome, supporting the notion that circadian misalignment amplifies adipose inflammation and cardiometabolic risk [28]. In parallel, immune cell populations within adipose depots exhibit time-dependent patterns of activity, suggesting that disruption of circadian control may directly contribute to inflammatory remodeling of adipose tissue [10].

Viewed in this context, adipose tissue operates as a circadian-regulated endocrine–metabolic–immune hub whose function depends not only on mass or location, but also on temporal integrity. Its heightened sensitivity to behavioral and environmental disruption provides a mechanistic link between circadian misalignment, insulin resistance, and chronic inflammation that extends beyond static measures of adiposity.

Human adipose tissue depots differ markedly in their circadian organization, with VAT showing greater vulnerability to rhythm disruption than subcutaneous adipose tissue (SAT), particularly in the setting of obesity. These depot-specific differences have important implications for insulin resistance, chronic inflammation, and cardiometabolic risk.

Direct 24 h profiling of human omental adipose tissue demonstrates that obesity profoundly alters the temporal expression of core clock genes, including CLOCK, BMAL1, PER1, CRY2, and REV-ERBα. Rather than simple attenuation, these changes reflect a reorganization of circadian rhythms within VAT. Altered rhythmicity of CRY2 and REV-ERBα correlates with waist circumference and other components of the metabolic syndrome, linking disruption of visceral circadian timing to clinically relevant metabolic risk [26].

Mechanistic human studies further indicate that circadian dysfunction in VAT is tightly coupled to inflammatory signaling. In individuals with obesity, omental adipose tissue exhibits impaired clock function characterized by reduced PER2 and REV-ERBα expression, loss of rhythmic BMAL1 chromatin binding, and lengthening of the circadian period. These alterations are driven, at least in part, by enhanced NF-κB (nuclear factor kappa B) activity, which directly interferes with clock gene regulation. Notably, pharmacological inhibition of NF-κB signaling restores circadian rhythmicity in human visceral adipose cells, supporting a causal role for inflammation in VAT clock disruption [29].

In contrast, SAT appears to retain greater circadian robustness. Comparative analyses of paired human SAT and VAT biopsies reveal higher PER1 expression and more stable temporal gene relationships in SAT, along with depot-specific associations between adiposity and clock gene expression [30]. These differences suggest that SAT is more resilient to metabolic stress, whereas VAT exhibits reduced circadian flexibility and heightened inflammatory sensitivity.

Additional human evidence reinforces this depot-specific pattern. Chronotype-associated circadian misalignment has been shown to translate into distinct inflammatory profiles in VAT but not SAT. In individuals with obesity, evening chronotypes exhibit significantly greater secretion of pro-inflammatory cytokines and chemokines from visceral fat, including interleukin-1 beta (IL-1β), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β), despite similar anthropometric and metabolic characteristics across chronotypes [31]. These inflammatory changes are accompanied by altered expression of core clock genes in VAT, indicating that behavioral circadian misalignment preferentially amplifies visceral inflammatory risk.

Functional consequences of depot-specific circadian regulation are particularly evident at the level of insulin signaling. Ex vivo studies of human adipose tissue explants demonstrate a robust intrinsic circadian rhythm in insulin sensitivity in SAT, with peak responsiveness around midday and a marked decline during the night. In contrast, VAT shows no significant circadian rhythm in insulin signaling, reflecting a loss of temporal metabolic regulation within this depot. This absence of rhythmic insulin responsiveness in visceral fat provides a mechanistic link between VAT circadian dysfunction and systemic insulin resistance [32].

Circadian regulation of adipokine expression also differs between depots. Although adiponectin and its receptors display circadian oscillations in both SAT and VAT, visceral fat exhibits reduced amplitude and delayed phase relative to subcutaneous tissue. Increasing adiposity is associated with further attenuation of adiponectin rhythmicity, particularly in VAT, aligning depot-specific circadian disruption with features of the metabolic syndrome [33].

REV-ERBα (NR1D1) functions as a key circadian regulator of adipose metabolism, particularly in visceral depots where it represses lipogenic gene expression and promotes β-oxidation through interactions with BMAL1 and PPARγ (peroxisome proliferator-activated receptor gamma) [34]. NR1D1 deficiency leads to metabolic inflexibility, ectopic lipid accumulation, and impaired thermogenesis, with pronounced effects in VAT and brown fat. Human polymorphisms such as rs2314339 have been linked to obesity and insulin resistance, underscoring the gene’s clinical relevance [33]. Also, pharmacologic activation of REV-ERBα (e.g., SR9009) restores metabolic rhythmicity, suppresses inflammation, and improves insulin sensitivity, thus highlighting its potential as a therapeutic target in circadian disruption contexts such as shift work and obesity [34,35].

The principal depot-specific differences in circadian regulation, metabolic responsiveness, and inflammatory signaling between SAT and VAT, as derived from human studies, are summarized in Table 1.

EAT and perivascular adipose tissue (PVAT) are anatomically specialized fat depots with direct paracrine access to the myocardium and vascular wall, positioning them as local modulators of cardiovascular structure and function. Unlike subcutaneous depots, EAT lies in immediate contact with the myocardium and coronary arteries without an intervening fascial plane, permitting bidirectional exchange of adipokines, cytokines, and metabolic signals. PVAT, in turn, surrounds large and small vessels and exerts local effects on vascular tone and inflammation.

Human studies consistently demonstrate that EAT adopts a pro-inflammatory secretory profile in cardiovascular disease. In patients undergoing coronary artery bypass surgery, epicardial fat exhibits increased macrophage infiltration and higher expression of inflammatory adipocytokines compared with non-cardiac adipose depots, supporting its role as a local amplifier of myocardial and coronary inflammation [36]. Importantly, this phenotype remains modifiable: statin therapy has been associated with reduced interleukin-6 expression in epicardial fat, thus emphasizing the dynamic and clinically relevant nature of EAT signaling [36].

High-resolution transcriptomic analyses further refine this picture. Single-nucleus RNA sequencing of pericoronary EAT from patients with coronary artery disease identifies disease-specific adipocyte and macrophage subpopulations with altered immune and secretory programs. Dysregulation of circadian clock-related pathways within EAT adipocytes accompanies these changes, suggesting that temporal disorganization may contribute to sustained paracrine stress on adjacent coronary vessels [37].

The clinical consequences of EAT dysfunction extend beyond atherosclerosis. Integration of human imaging and pathological data supports the concept of an “epicardial adipose inflammatory triad,” in which EAT expansion and inflammation promote coronary atherosclerosis, atrial remodeling with arrhythmogenic vulnerability, and ventricular stiffening characteristic of heart failure with preserved ejection fraction [38]. Spatial heterogeneity across epicardial fat depots appears to influence the dominant phenotype, linking regional adipose inflammation to site-specific cardiac pathology.

Consistent with this framework, observational and mechanistic human studies implicate EAT as a contributor to atrial fibrillation. Pro-inflammatory and pro-fibrotic mediators released from epicardial fat infiltrate adjacent atrial myocardium, facilitating structural and electrical remodeling that lowers the threshold for arrhythmia initiation and maintenance [39]. These effects emphasize the relevance of EAT as a locally active adipose compartment rather than a passive bystander.

Building on the concept of depot-specific “local clocks,” PVAT has emerged as a time-structured paracrine organ capable of tuning vascular function across the day–night cycle. A key mechanistic advance is the identification of an intrinsic circadian clock within PVAT adipocytes, where BMAL1 transcriptionally regulates angiotensinogen expression and local angiotensin II availability. In brown-adipocyte–targeted Bmal1 or Agt knockout models, blood pressure is selectively reduced during the resting phase, producing a pronounced “super-dipper” phenotype; ex vivo, PVAT from wild-type mice increases aortic ring contractility in an endothelium-independent manner, an effect attenuated when Bmal1 is deleted in PVAT adipocytes [40].

Systemic clock disruption can further reprogram PVAT toward vascular dysfunction. In hepatocyte-specific Bmal1 knockout mice, liver clock perturbation alters circulating metabolic signals and remodels thoracic PVAT gene expression, including regulators of lipid handling and thermogenic programs. Under these conditions, PVAT selectively impairs endothelial function: acetylcholine-mediated vasorelaxation is reduced when PVAT remains attached, yet endothelial responsiveness is preserved once PVAT is removed [41]. This pattern supports a model in which mistimed systemic metabolism imprints on PVAT, reshaping the vasoactive environment presented to the vessel wall.

In atherometabolic disease, PVAT behaves as a double-edged layer. Under physiological conditions, it supports vascular homeostasis through anticontractile and anti-atherogenic mediators, as well as thermogenic lipid clearance. In obesity and metabolic dysfunction, PVAT becomes inflamed, loses thermogenic capacity, and releases pro-inflammatory adipokines and cytokines that promote endothelial dysfunction and plaque progression [42]. Framed in temporal terms, PVAT and by extension peri-coronary and peri-vascular fat, acts as a circadian effector tissue whose time-dependent paracrine outputs may influence atherosclerosis trajectories and downstream phenotypes such as arrhythmia susceptibility and heart failure remodeling.

EAT and PVAT represent anatomically specialized adipose depots with direct paracrine access to the myocardium and vascular wall, positioning them as local modulators of cardiovascular structure and function. Unlike subcutaneous depots, EAT lies in direct contact with the myocardium and coronary arteries without a separating fascia, enabling bidirectional exchange of cytokines, adipokines, and metabolic signals. The principal circadian and paracrine features distinguishing epicardial and perivascular adipose tissue are summarized in Table 2.

Adipose tissue lipid storage and mobilization are intrinsically time-structured processes governed by circadian regulation. In humans, a defined subset of circulating and adipose-derived lipid species exhibits robust 24 h rhythmicity, reflecting coordinated temporal control of lipolysis, lipogenesis, and lipid trafficking. Lipidomic profiling of human subcutaneous adipose tissue and matched serum samples indicates that approximately 8% of lipid metabolites oscillate diurnally under metabolically healthy conditions. These rhythms are markedly disrupted in type 2 diabetes, with reduced amplitudes, phase shifts, and loss of synchrony between adipose tissue and circulating lipid pools, despite relatively stable mean lipid concentrations across the day. Time-resolved analyses reveal temporal disorganization affecting phospholipids, sphingolipids, and glycerolipid intermediates, indicating impaired coordination between adipose lipid handling and systemic lipid availability [43].

Circadian misalignment itself is sufficient to induce maladaptive lipid metabolic programs in humans. Experimental inversion of the behavioral cycle rapidly alters transcriptional pathways regulating fatty acid uptake and metabolism, accompanied by reduced insulin sensitivity and increased circulating free fatty acids [44]. Such behavioral misalignment often reflects underlying light-driven circadian phase delays, particularly those induced by evening or nocturnal light exposure that suppresses melatonin signaling, thereby desynchronizing central circadian timing cues from adipocyte lipid-metabolic clocks.

Mechanistic insight from experimental models further clarifies the consequences of disrupted adipose clocks. In mice with adipose-specific deletion of the core clock component BMAL1, diurnal variation in lipolysis is abolished, resulting in flattened free fatty acid and glycerol release profiles and increased triglyceride accumulation within adipocytes [45]. Loss of rhythmic lipid turnover is accompanied by elevated circulating lipid levels and ectopic fat deposition in the liver and skeletal muscle, indicating a failure of adipose tissue to buffer systemic lipid fluxes. In parallel, reduced adipogenic capacity and impaired adipose tissue expandability further redirect excess lipids toward non-adipose tissues under metabolic stress [46].

Adipose tissue functions as a circadian-regulated endocrine organ, with adipokine secretion following defined daily rhythms that coordinate metabolic and inflammatory signaling. Circadian misalignment disrupts both the timing and amplitude of adipokine release, contributing to metabolic dysfunction independently of fat mass.

Leptin exhibits a well-characterized diurnal rhythm in humans, with higher nocturnal and lower daytime concentrations reflecting energy storage status. Circadian disruption and insufficient sleep attenuate this rhythmicity, producing flattened or phase-shifted leptin profiles. Even when mean leptin levels remain unchanged, loss of temporal signaling is associated with impaired satiety control and increased energy intake, consistent with a form of circadian leptin resistance. Adiponectin, an insulin-sensitizing and anti-inflammatory adipokine, also displays circadian variation under physiological conditions. Sleep disturbance and circadian misalignment are associated with reduced adiponectin levels, particularly in individuals with obesity, further compromising insulin sensitivity and favoring pro-inflammatory metabolic signaling [47,48].

Melatonin signaling represents a key upstream regulator linking circadian timing to adipokine rhythmicity and metabolic control. Melatonin secretion is tightly coupled to the light–dark cycle, peaks during the biological night, and exhibits an inverse temporal relationship with insulin secretion and glucose tolerance in humans. Disruption of melatonin rhythms by evening or nocturnal light exposure shifts internal circadian phase and alters downstream metabolic signaling pathways, including those governing leptin sensitivity and glucose handling [20].

Circadian disruption additionally reshapes the inflammatory secretory profile of adipose tissue. In human visceral fat, evening chronotype is associated with increased release of pro-inflammatory cytokines and chemokines, including IL-1β, IL-8, MCP-1, and MIP-1β, despite comparable anthropometric and metabolic characteristics [31]. These changes coincide with altered clock gene expression, linking local circadian disruption to inflammatory adipokine output.

Interindividual genetic variation in melatonin signaling further modulates susceptibility to these endocrine and metabolic effects. A common variant near the melatonin receptor gene MTNR1B (encoding the MT2 receptor) is robustly associated with elevated fasting plasma glucose, impaired early insulin secretion, and increased risk of type 2 diabetes across multiple large human cohorts, independent of obesity. MTNR1B is expressed in central circadian regulatory regions, including the suprachiasmatic nucleus, as well as in human pancreatic islets and beta cells, providing a mechanistic link between light-regulated melatonin signaling, circadian timing, and metabolic control. These findings support the concept that genetic variation in melatonin receptor signaling can influence individual vulnerability to metabolic consequences of circadian misalignment, including altered adipokine signaling and glucose homeostasis [49].

Human interventional studies indicate that temporal realignment can partially reverse these endocrine and inflammatory alterations; time-restricted eating (TRE) reduces circulating leptin and TNF-α (tumor necrosis factor alpha) levels, with more variable effects on IL-6 (interleukin-6) and adiponectin, despite modest weight loss [50]. Leptin appears particularly sensitive to temporal interventions, especially in individuals with overweight or obesity. In a randomized trial, early time-restricted eating produced greater reductions in leptin concentrations than late eating under comparable caloric restriction, highlighting sensitivity to circadian phase alignment rather than energy balance alone [51]. By contrast, circadian disruption through night-shift work produces opposing endocrine and inflammatory effects. In women exposed to night shifts, disturbed melatonin rhythms are accompanied by increased leptin concentrations and elevations in pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, independent of long-term changes in body composition [52]. Therefore, it is safe to conclude that both environmental circadian disruption and genetic variation in melatonin signaling pathways shape adipokine rhythmicity and metabolic risk in humans [20,47].

These key features of adipokine circadian regulation and their disruption are summarized in Table 3.

Circadian regulation plays a central role in coordinating immune cell behavior within adipose tissue, and its disruption promotes a shift from adaptive immune surveillance toward chronic inflammatory remodeling. Experimental models of prolonged circadian misalignment demonstrate that disruption of light–dark cycles induces immune activation in both visceral and subcutaneous adipose depots, characterized by macrophage infiltration, crown-like structure formation, and loss of normal time-of-day-dependent gene regulation. These immune changes accompany adipocyte hypertrophy and precede overt metabolic dysfunction, indicating that immune remodeling represents an early response to circadian disruption [53].

Immune cell trafficking and function within adipose tissue are tightly regulated by circadian mechanisms. Regulatory T cells (Tregs) residing in visceral adipose tissue exhibit robust, cell-intrinsic circadian oscillations that are absent in lymphoid tissues, governing their activation state, metabolic fitness, and survival within the adipose microenvironment. Disruption of core clock components in Tregs abolishes diurnal variation in adipose tissue lipolysis and promotes constitutive immune activation, identifying circadian programming of tissue-resident immune cells as a key determinant of adipose immune homeostasis [54]. Sustained circadian misalignment shifts this balance toward chronic inflammation and fibrotic remodeling. In long-term models of shiftwork-like circadian disruption, adipose tissue shows upregulation of inflammatory and extracellular matrix-related gene programs, increased collagen deposition, and suppression of rhythmic transcriptional activity [53]. These fibrotic changes reduce tissue plasticity, constrain adipocyte expansion, and amplify inflammatory signaling, thereby accelerating adipose dysfunction.

Human data support the relevance of these pathways. Molecular profiling of abdominal subcutaneous adipose tissue following endurance exercise reveals rapid, intensity-dependent regulation of immune and extracellular matrix gene networks, including programs linked to angiogenesis, matrix remodeling, and reduced pro-inflammatory macrophage signaling [55]. Rather than being static, human adipose tissue remains responsive, with the capacity to reshape its immune and structural landscape when exposed to physiological stimuli.

Macrophages represent a critical interface linking circadian disruption to immune and fibrotic remodeling. These cells possess autonomous circadian clocks that regulate lipid and glucose metabolism in a time-of-day-dependent manner, thereby shaping inflammatory responsiveness within adipose tissue. Disruption of macrophage clock genes alters metabolic programming, favoring glycolytic, pro-inflammatory polarization with sustained cytokine production and impaired resolution of inflammation. Through secretion of matrix-modifying enzymes and profibrotic mediators, chronically activated macrophages promote extracellular matrix accumulation and loss of tissue flexibility [56].

Hypoxia further reinforces immune and fibrotic remodeling under circadian dysregulation. Altered oxygen availability disrupts core clock gene expression through hypoxia-inducible factors that interact directly with circadian transcriptional machinery, leading to dampened oscillatory amplitude and inter-tissue desynchrony. Hypoxia-driven circadian impairment is associated with enhanced inflammatory signaling, oxidative stress, and sympathetic activation, creating a feed-forward cycle that limits adipose tissue expandability and accelerates metabolic deterioration [57].

MHO is increasingly recognized as a transient state rather than a stable phenotype. Although individuals with MHO may initially display preserved insulin sensitivity, limited visceral and ectopic fat accumulation, and maintained adipose tissue expandability, longitudinal studies show that a substantial proportion progress to metabolically unhealthy obesity (MUO) over time. This instability stresses the need to identify determinants of metabolic deterioration that extend beyond static measures of body mass.

A central feature of this transition is the gradual loss of adipose tissue adaptability. Under conditions of positive energy balance, effective expansion of subcutaneous adipose tissue limits lipid overflow to visceral depots and non-adipose tissues, thereby preserving insulin sensitivity. When this buffering capacity is exceeded or disrupted, lipid spillover ensues, accompanied by inflammation, adverse adipokine signaling, and metabolic impairment [11,12].

Circadian misalignment, driven by disrupted sleep–wake patterns, irregular feeding schedules, and attenuation of daily metabolic rhythms, appears to accelerate this process. Chronic exposure to late-night light, delayed sleep timing, and irregular feeding can progressively shift chronotype toward a later circadian phase, thereby destabilizing adipose tissue rhythmicity and weakening metabolic resilience. Sleep disruption and mistimed food intake impair the temporal regulation of adipose lipid handling and adipokine secretion, weakening coordination between energy storage and mobilization. Even in the absence of marked weight gain, loss of circadian control increases susceptibility to insulin resistance and low-grade inflammation [11]. As rhythmic adipose function deteriorates, subcutaneous fat becomes less effective as a metabolic buffer, favoring visceral fat expansion and ectopic lipid deposition—key features of MUO.

Clinical and mechanistic syntheses support this model of phenotype evolution. MHO is uncommon when stringent metabolic criteria are applied and frequently represents an intermediate stage preceding metabolic decline, characterized by worsening insulin sensitivity, increasing hepatic steatosis, and progressive adipose tissue dysfunction. Behavioral factors such as physical inactivity, weight gain, and impaired sleep contribute to this trajectory, highlighting the importance of temporal and lifestyle influences on metabolic resilience in obesity [58]. Cardiometabolic risk tracks more closely with fat distribution and adipose tissue dysfunction than with BMI itself, with visceral and ectopic fat strongly associated with progression toward dyslipidemia, glucose intolerance, and cardiovascular disease [59]. These observations are consistent with a framework in which disruption of adipose expandability and metabolic timing drives the shift from MHO to MUO.

Viewed through this lens, circadian misalignment functions as a permissive factor for phenotype conversion by eroding adipose tissue flexibility and metabolic resilience. The transition from metabolically healthy to unhealthy obesity reflects not simply cumulative fat gain, but a breakdown in the temporal organization of adipose tissue biology driven by disrupted sleep and feeding rhythms. This perspective reinforces the limitations of BMI-based categorization and supports circadian-aware approaches to preserving metabolic health in individuals with obesity.

MUNW describes individuals whose body mass index falls within the conventional normal range yet who exhibit insulin resistance, dyslipidemia, hypertension, hepatic steatosis, and elevated cardiometabolic risk. This phenotype exposes a fundamental limitation of BMI-based classification and reinforces the principle that metabolic health is shaped by adipose tissue function and fat distribution rather than body mass alone [11,12,59].

Genetic and metabolic data indicate that MUNW represents a biologically distinct phenotype rather than a statistical anomaly. Genome-wide analyses show that carriers of insulin resistance–associated alleles may have lower BMI but display increased visceral-to-subcutaneous fat ratios, reduced adiponectin levels, hepatic steatosis, and heightened risk of type 2 diabetes and coronary artery disease [60]. These features resemble aspects of partial lipodystrophy and point to impaired subcutaneous adipose tissue expandability as a central driver of metabolic dysfunction in the absence of overt obesity.

Circadian disruption appears to act as a critical, and often overlooked, modifier of this phenotype. Epidemiologic studies consistently link insufficient or irregular sleep, often driven by evening light exposure and delayed circadian phase, to impaired glucose tolerance, insulin resistance, hypertension, and dyslipidemia, even among individuals with normal body weight [61]. Such findings suggest that sleep loss and circadian misalignment can reveal latent metabolic vulnerability that remains hidden when risk assessment relies on BMI alone.

Mechanistic evidence supports a causal role for temporal misalignment. Experimental models of simulated shift work or behavioral circadian disruption induce rapid deterioration of cardiometabolic markers in healthy, lean adults, including impaired glucose regulation, inflammatory activation, endothelial dysfunction, and prothrombotic changes. These effects emerge within days and occur independently of changes in adiposity, underscoring the sensitivity of metabolic homeostasis to circadian timing [62].

In MUNW, chronodisruption likely contributes by destabilizing adipose tissue rhythmicity and endocrine signaling. Disruption of sleep–wake and feeding cycles in the context of delayed circadian phase impairs time-dependent regulation of lipolysis, adipokine secretion, and insulin sensitivity, reducing the capacity of subcutaneous adipose tissue to buffer energy excess. Lipid partitioning consequently shifts toward visceral and ectopic depots, promoting hepatic steatosis and systemic insulin resistance despite preserved BMI. Altered leptin signaling and reduced adiponectin further reinforce this trajectory [11,60].

The MUNW phenotype challenges the assumption that normal weight confers cardiometabolic protection. Individuals with adverse fat distribution and impaired circadian alignment may accumulate substantial risk while remaining undetected by conventional screening approaches. Framing MUNW as a circadian-sensitive metabolic phenotype highlights chronodisruption as a modifiable driver of disease and supports a shift toward functional, rather than anthropometric, definitions of metabolic risk.

Chrononutrition strategies, particularly time-restricted feeding (TRF), have gained attention as clinically applicable interventions capable of restoring metabolic rhythmicity independently of substantial weight loss. Aligning food intake with earlier circadian phases improves metabolic regulation by reinforcing endogenous rhythms in substrate utilization, hormonal signaling, and energy expenditure [71]. Also, several weeks of early time-restricted feeding (Etrf) improved insulin sensitivity, lowered fasting insulin concentrations, and reduced markers of oxidative stress and inflammation, despite minimal weight loss. These benefits were accompanied by improved diurnal alignment of glucose regulation, suggesting restoration of temporal coordination between nutrient intake and metabolic processing rather than simple caloric restriction [72]. Longer-term interventions indicate that TRF may also influence adipose tissue distribution and cardiometabolic risk. TRF reduced visceral adipose tissue and improved features of the metabolic syndrome compared with control diets, even when energy intake was similar between groups [73].

Concerns regarding the feasibility and safety of prolonged daily fasting have been addressed by recent clinical data, the results being that early, late, or self-selected time-restricted eating (TRE) schedules did not adversely affect sleep duration, sleep quality, mood, or quality of life in adults with overweight or obesity [74]. This absence of negative effects on sleep and psychosocial outcomes supports the long-term acceptability of TRE in routine cardiometabolic care.

Emerging evidence also indicates that the metabolic impact of TRE depends on the timing of the eating window relative to endogenous circadian rhythms. In a three-month randomized intervention stratified by chronotype, it was determined that early TRE combined with energy restriction produced greater reductions in fat mass, fasting glucose, metabolic age, and diastolic blood pressure than late TRE or energy restriction alone, despite similar weight loss across groups [75]. It is safe to suggest, based on these results, that early alignment of food intake with circadian metabolic peaks enhances adipose lipid handling and cardiometabolic efficiency.

Recent syntheses of human TRE interventions further support consistent improvements in body composition, visceral adiposity, and cardiometabolic risk markers, while highlighting interindividual variability related to chronotype, baseline metabolic status, and adherence [76]. Rather than acting solely through energy reduction, time-restricted eating, most notably when implemented earlier in the day, appears to improve adipose tissue function by restoring temporal alignment of metabolic processes, offering a clinically relevant alternative to calorie-focused dietary strategies.

Pharmacological treatment of metabolic disease increasingly intersects with circadian biology, both through drug mechanisms of action and through time-dependent variation in absorption, distribution, and efficacy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) illustrate this interplay, as they engage pathways under strong circadian control, including insulin secretion, appetite regulation, gastrointestinal motility, and adipose tissue metabolism. GLP-1–based therapies provide coordinated benefits across glycemic control, body weight, and cardiometabolic risk, while also influencing hormonal and autonomic systems with pronounced diurnal variation [77].

The importance of timing is particularly evident for orally administered GLP-1Ras, as systemic exposure to oral semaglutide is highly sensitive to fasting duration before and after dosing, with even modest deviations from recommended schedules markedly reducing bioavailability [78]. This finding reflects the circadian regulation of gastric emptying, intestinal motility, and splanchnic blood flow, and provides a practical explanation for interindividual variability in treatment response observed in routine care.

More broadly, principles of chronotherapy are gaining relevance across endocrine pharmacology. Circadian rhythms influence hormone secretion, receptor sensitivity, intracellular signaling, and drug metabolism, thereby shaping both efficacy and adverse-effect profiles. Aligning pharmacological interventions with endogenous biological timing has improved outcomes in several endocrine contexts and may hold similar promise in obesity and cardiometabolic disease [79].

Viewed in this context, pharmacological modulation of circadian metabolism should be considered a temporally adaptable strategy that integrates drug choice, formulation, and dosing time. Incorporating chronotherapeutic principles into metabolic treatment algorithms offers a rational approach to enhancing therapeutic consistency and clinical benefit by synchronizing pharmacology with circadian physiology.

Current cardiometabolic risk stratification relies largely on static measurements that fail to capture temporal variation in physiology and behavior. Accumulating human evidence indicates that circadian misalignment represents an independent and clinically relevant contributor to cardiometabolic risk. Experimental circadian disruption in healthy adults rapidly impairs glucose tolerance, increases inflammatory activity, induces endothelial dysfunction, and promotes a prothrombotic state, even in the absence of changes in body weight or adiposity [60].

Advances in circadian biomarker development now permit objective assessment of internal biological time in clinical and research settings. Transcriptomic signatures derived from peripheral blood can estimate circadian phase with high accuracy from a limited number of samples, enabling quantification of circadian alignment independent of self-reported sleep or behavioral timing. Such tools identify individuals whose internal clocks are misaligned with external demands, a state associated with elevated cardiometabolic risk even among BMI-normal or otherwise healthy populations [80].

Complementary approaches using multi-tissue transcriptomic and metabolomic profiling also support the concept of a systemic circadian phenotype linked to metabolic disease risk. These methods provide a mechanistic bridge between molecular circadian disruption and downstream abnormalities in insulin sensitivity, lipid metabolism, and inflammatory signaling. When integrated with imaging-based assessment of adipose distribution or ectopic fat burden, circadian biomarkers may refine risk stratification by identifying individuals in whom temporal dysregulation amplifies structural and metabolic susceptibility [81,82].

From a translational standpoint, circadian-informed risk assessment offers several advantages. It enables earlier identification of risk states that precede overt disease, supports personalization of preventive strategies such as meal timing, physical activity, and pharmacotherapy, and complements existing clinical, imaging, and omics-based tools within a precision medicine framework. Framing cardiometabolic risk as a function of both magnitude and timing may improve detection of vulnerable individuals and guide temporally targeted interventions aimed at preserving metabolic resilience.