Diurnal rhythms in the white adipose tissue transcriptome are disturbed in obese individuals with type 2 diabetes compared with lean control individuals

Abstract

Aims/hypothesis Animal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes. Methods In a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3 days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing. Results The core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway 'EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations. Conclusions/interpretation Diurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling. Data availability The raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674).

Neurogenetic basis for circadian regulation of metabolism by the hypothalamus

“…This suggests that misalignment of sleep/wake and feeding/fasting cycles increases the risk of obesity in humans. This could also indicate that metabolic homeostasis influences circadian phase of entrainment, in line with the observation that obesity in high-fat diet (HFD)-fed mice causes disruption of circadian rhythms (Kohsaka et al 2007;Hatori et al 2012) and as also indirectly supported by clinical studies of subjects with metabolic disease such as obesity and type 2 diabetes (Otway et al 2011;Stenvers et al 2019).…”

High-Energy Diet and Shorter Light Exposure Drives Markers of Adipocyte Dysfunction in Visceral and Subcutaneous Adipose Depots of Psammomys obesus

“…Development of T2DM is associated with dysfunctional adipose tissue phenotype, characterized by increased adipocyte size and a pro-inflammatory response. Increasing evidence shows that disruption of circadian rhythms contributes to disease progression, and it was recently found that daily rhythms in the white adipose tissue transcriptome are disturbed in individuals with T2DM compared with lean individuals [14]. In this study we have used the Psammomys obesus sand rat, a unique animal model that mimics T2DM development in humans.…”

“…Shift work has been shown to have significant negative health impacts, with numerous studies reporting an association of shift work with elevated risks for overweight, metabolic syndrome and T2DM [8][9][10][11]. Increasing evidence shows that disruption of circadian rhythms increases the risk of many chronic diseases including T2DM [12,13] and diurnal rhythms in the white adipose tissue transcriptome are disturbed in obese individuals with T2DM [14]. Animal models of chronodisruption that include scheduled food access, high fat diet, mistimed activity, sleep disruption and light exposure all show significant impacts on the development of obesity, metabolic syndrome, impaired glucose metabolism and hyperglycemia [6].…”

The Circadian Syndrome: is the Metabolic Syndrome and much more!

“…Given the close linkage of obesity, especially central (abdominal) as a key component of the Metabolic Syndrome, obesity plays an important role in risk of T2DM and insulin sensitivity as well as CVD [39]. A role for circadian rhythms, including the circadian clock within the adipocytes, in the development of obesity was described [17,[71][72][73]. As noted earlier, there is also a close relationship with obesity in terms of risk for obstructive sleep apnoea, a key comorbidity.…”

“…Herein we discuss research findings relating to the proposed Circadian Syndrome risk components and comorbidities (Table 2). Hypertension Lack of nocturnal decline in blood pressure [30,62] High blood pressure [22] Lipids Disrupted lipid homeostasis [69,70] Obesity Disrupted diurnal rhythms in the white adipose tissue transcriptome [73] Obesity [22] Blood glucose levels Disrupted daily rhythms in blood glucose levels and glucose intolerance [17,21,75] Disrupted daily rhythms in blood glucose levels and glucose intolerance [22] Fatty liver Disrupted triglyceride accumulation, inflammation, oxidative stress and mitochondrial dysfunction [29] Depression Circadian disruption increases the incidences of depression [86,87] Circadian disruption increases the incidences of depression [22,83,84,[105][106][107][108][109][110] Sleep disturbances Circadian disturbances result in sleep loss and mistimed sleep [56,97] Proposing a Circadian Syndrome: Cardiovascular-related components Circadian oscillations have been reported for both physiological CVD regulation including heart rate and blood pressure [57], for cardiac disorders including arrythmias [58,59], and there is circadian variation in frequency of onset of myocardial infarction and sudden cardiac death [19,60].…”