Laminin-α4 Negatively Regulates Adipocyte Beiging Through the Suppression of AMPKα in Male Mice.

Laminin-α4 (LAMA4) is an extracellular matrix protein implicated in the regulation of adipocyte differentiation and function. Prior research describes a role for LAMA4 in modulating adipocyte thermogenesis and uncoupling protein-1 (UCP1) expression in white adipose; however, the mechanisms involved are poorly understood. Here, we describe that Lama4 knockout mice (Lama4-/-) exhibit heightened mitochondrial biogenesis and peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) expression in subcutaneous white adipose tissue (sWAT).

Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity.

Obesity affects nearly one billion globally and can lead to life-threatening sequelae. Consequently, there is an urgent need for novel therapeutics. We have previously shown that laminin, alpha 4 () knockout in mice leads to resistance to adipose tissue accumulation; however, the relationship between and obesity in humans has not been established.

Laminins in metabolic tissues.

Laminins are extracellular matrix proteins that reside in the basement membrane and provide structural support in addition to promoting cellular adhesion and migration. Through interactions with cell surface receptors, laminins stimulate intracellular signaling cascades which direct specific survival and differentiation outcomes. In metabolic tissues such as the pancreas, adipose, muscle, and liver, laminin isoforms are expressed in discrete temporal and spatial patterns suggesting that certain isoforms may support the development and function of particular metabolic cell types.

Integrins and extracellular matrix proteins modulate adipocyte thermogenic capacity.

Obesity and the metabolic disease epidemic has led to an increase in morbidity and mortality. A rise in adipose thermogenic capacity via activation of brown or beige fat is a potential treatment for metabolic diseases. However, an understanding of how local factors control adipocyte fate is limited.

A 3D human adipose tissue model within a microfluidic device.

An accurate in vitro model of human adipose tissue could assist in the study of adipocyte function and allow for better tools for screening new therapeutic compounds. Cell culture models on two-dimensional surfaces fall short of mimicking the three-dimensional in vivo adipose environment, while three-dimensional culture models are often unable to support long-term cell culture due, in part, to insufficient mass transport. Microfluidic systems have been explored for adipose tissue models.

SMRT Regulates Metabolic Homeostasis and Adipose Tissue Macrophage Phenotypes in Tandem.

The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor, regulating the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of the role of SMRT in the adipocyte has been well-established, our comprehensive understanding of its in vivo function in the context of homeostatic maintenance is limited due to contradictory phenotypes yielded by prior generalized knockout mouse models. Multiple such models agree that SMRT deficiency leads to increased adiposity, although the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable.

APP-Mediated Signaling Prevents Memory Decline in Alzheimer's Disease Mouse Model.

Amyloid precursor protein (APP) and its metabolites play key roles in Alzheimer's disease (AD) pathophysiology. Whereas short amyloid-β (Aβ) peptides derived from APP are pathogenic, the APP holoprotein serves multiple purposes in the nervous system through its cell adhesion and receptor-like properties. Our studies focused on the signaling mediated by the APP cytoplasmic tail.

The Absence of Laminin α4 in Male Mice Results in Enhanced Energy Expenditure and Increased Beige Subcutaneous Adipose Tissue.

Laminin α4 (LAMA4) is located in the extracellular basement membrane that surrounds each individual adipocyte. Here we show that LAMA4 null (Lama4-/-) mice exhibit significantly higher energy expenditure (EE) relative to wild-type (WT) mice at room temperature and when exposed to a cold challenge, despite similar levels of food intake and locomotor activity. The Lama4-/- mice are resistant to age- and diet-induced obesity.

Loss of presenilin function is associated with a selective gain of APP function.

Presenilin 1 (PS1) is an essential γ-secretase component, the enzyme responsible for amyloid precursor protein (APP) intramembraneous cleavage. Mutations in PS1 lead to dominant-inheritance of early-onset familial Alzheimer's disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic Aβ production, the importance of other APP metabolites and γ-secretase substrates in the etiology of the disease has not been confirmed.