Daily Endocrinology Research Analysis

Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

UNLABELLED: The microtubule network in β-cells attenuates insulin secretion by pulling insulin secretory granules away from the plasma membrane. Thus, high-glucose-induced microtubule remodeling is required for robust glucose-stimulated insulin secretion. We now demonstrate that hormones secreted by α-cells regulate microtubule dynamics in β-cells through receptors for glucagon (GcgR) and glucagon-like peptide 1 (GLP-1R). Activation of GcgR or GLP-1R destabilizes microtubules in β-cells, accompanied by increased insulin secretion. In contrast, inhibiting these receptors attenuates high-glucose-induced microtubule destabilization and decreases secretion. Supporting the physiological significance of this regulation, β-cells in islets with a higher α-cell-to-β-cell ratio exhibit more dynamic microtubules than those with a lower ratio, and a high-fat diet challenge in mice, which can compromise β-cell secretion, attenuates this effect in their islets. Within individual islets, β-cells located near α-cells show faster microtubule remodeling upon glucose stimulation than those more distant from α-cells. Consequently, islets with a higher α-cell-to-β-cell ratio secrete more insulin in response to glucose stimulation and plasma membrane depolarization, results recapitulated by exogenous glucagon stimulation or chemically induced microtubule destabilization in islets with lower α-cell-to-β-cell ratios. These combined results suggest that α-cells use glucagon-mediated and/or GLP-1-mediated paracrine signaling to fine-tune β-cell secretion via microtubule remodeling. ARTICLE HIGHLIGHTS: Glucagon/glucagon-like peptide 1 sensitizes glucose-induced microtubule remodeling in β-cells. Microtubule density in islets inversely correlates with the α-cell-to-β-cell ratio. Glucose-stimulated insulin secretion levels in single islets positively correlate with their α-cell-to-β-cell ratio. Glucagon and microtubule destabilization mobilize the same granule pool.

OBJECTIVE: We assessed the association between timing of moderate-to-vigorous physical activity (MVPA) with incident type 2 diabetes (T2D) and glycemic measures. RESEARCH DESIGN AND METHODS: Regression models were used to assess associations between accelerometer-derived MVPA timing and incident T2D in UK Biobank (UKB) (n = 84,528, prospective), prevalent diabetes, and glycemic measures in the National Health and Nutrition Examination Survey (NHANES) (n = 6,998, cross-sectional). RESULTS: In UKB, with early morning (0500-0959) MVPA as reference and before adjustment for total MVPA, "variable-timing" MVPA was associated with the lowest incident T2D risk; while after adjustment, afternoon-evening MVPA (1500-2400) showed the lowest incident T2D risk. In NHANES, afternoon/early evening MVPA was weakly associated with more favorable glycemic measures and lower diabetes prevalence after adjustment for total MVPA. CONCLUSIONS: When keeping total MVPA volume constant, clustering MVPA in the afternoon-evening was associated with the strongest reduction in incident T2D risk, fewer prevalent diabetes, and more favorable glycemic measures.