Adipocyte gene expression in obesity - insights gained and challenges ahead.

White adipocytes possess extraordinary plasticity with an unparalleled capacity to expand in size with nutritional overload. Several lines of evidence indicate that limitations to this plasticity, as found in both lipodystrophy and obesity, drive several of the comorbidities of these disease, thereby underscoring the need to understand the mechanisms of healthy and unhealthy adipose expansion. Recent single-cell technologies and studies of isolated adipocytes have allowed researchers to gain insight into the molecular mechanisms of adipocyte plasticity.

Lipolysis regulates major transcriptional programs in brown adipocytes.

β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in cultured brown adipocytes. Here we show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals.

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand.

Plasticity of Epididymal Adipose Tissue in Response to Diet-Induced Obesity at Single-Nucleus Resolution.

Adipose tissues display a remarkable ability to adapt to the dietary status. Here, we have applied single-nucleus RNA-seq to map the plasticity of mouse epididymal white adipose tissue at single-nucleus resolution in response to high-fat-diet-induced obesity. The single-nucleus approach allowed us to recover all major cell types and to reveal distinct transcriptional stages along the entire adipogenic trajectory from preadipocyte commitment to mature adipocytes.

C57BL/6J substrain differences in response to high-fat diet intervention.

C57BL/6J-related mouse strains are widely used animal models for diet-induced obesity (DIO). Multiple vendors breed C57BL/6J-related substrains which may introduce genetic drift and environmental confounders such as microbiome differences. To address potential vendor/substrain specific effects, we compared DIO of C57BL/6J-related substrains from three different vendors: C57BL/6J (Charles Rivers), C57BL/6JBomTac (Taconic Bioscience) and C57BL/6JRj (Janvier).

Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes.

Utilizing the thermogenic capacity of brown adipose tissue is a potential anti-obesity strategy; therefore, the mechanisms controlling expression of thermogenesis-related genes are of interest. Pyruvate kinase (PK) catalyzes the last step of glycolysis and exists as four isoenzymes: PK, liver, PK, red blood cell, PK, muscle (PKM1 and PKM2). PKM2 has both glycolytic and nuclear functions.

GSK3 is a negative regulator of the thermogenic program in brown adipocytes.

Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads to an increase in oxygen consumption and induction of a thermogenic gene program that includes uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identified glycogen synthase kinase 3 (GSK3) as a negative regulator of basal and β-adrenergically stimulated Fgf21 expression in cultured brown adipocytes.