Hangry hairs: intermittent fasting linked to hair loss
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A force-sensitive adhesion GPCR is required for equilibrioception
Equilibrioception (sensing of balance) is essential for mammals to perceive and navigate the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells is crucial for detecting position and motion. Here, we identify the G protein-coupled receptor (GPCR) LPHN2/ADGRL2, expressed on the apical membrane of utricular hair cells, as essential for maintaining normal balance. Loss of LPHN2 specifically in hair cells impaired both balance behavior and the MET response in mice. Functional analyses using hair-cell-specific Lphn2-knockout mice and an LPHN2-specific inhibitor suggest that LPHN2 regulates tip-link-independent MET currents at the apical surface of utricular hair cells. Mechanistic studies in a heterologous system show that LPHN2 converts force stimuli into increased open probability of transmembrane channel-like protein 1 (TMC1). LPHN2-mediated force sensation triggers glutamate release and calcium signaling in utricular hair cells. Importantly, reintroducing LPHN2 into the hair cells of Lphn2-deficient mice restores vestibular function and MET response. Our data reveal that a mechanosensitive GPCR is required for equilibrioception.
Effect of broccoli sprout extract and baseline gut microbiota on fasting blood glucose in prediabetes: a randomized, placebo-controlled trial
More effective treatments are needed for impaired fasting glucose or glucose intolerance, known as prediabetes. Sulforaphane is an isothiocyanate that reduces hepatic gluconeogenesis in individuals with type 2 diabetes and is well tolerated when provided as a broccoli sprout extract (BSE). Here we report a randomized, double-blind, placebo-controlled trial in which drug-naive individuals with prediabetes were treated with BSE (n = 35) or placebo (n = 39) once daily for 12 weeks. The primary outcome was a 0.3 mmol l−1 reduction in fasting blood glucose compared with placebo from baseline to week 12. Gastro-intestinal side effects but no severe adverse events were observed in response to treatment. BSE did not meet the prespecified primary outcome, and the overall effect in individuals with prediabetes was a 0.2 mmol l−1 reduction in fasting blood glucose (95% confidence interval −0.44 to −0.01; P = 0.04). Exploratory analyses to identify subgroups revealed that individuals with mild obesity, low insulin resistance and reduced insulin secretion had a pronounced response (0.4 mmol l−1 reduction) and were consequently referred to as responders. Gut microbiota analysis further revealed an association between baseline gut microbiota and pathophysiology and that responders had a different gut microbiota composition. Genomic analyses confirmed that responders had a higher abundance of a Bacteroides-encoded transcriptional regulator required for the conversion of the inactive precursor to bioactive sulforaphane. The abundance of this gene operon correlated with sulforaphane serum concentration. These findings suggest a combined influence of host pathophysiology and gut microbiota on metabolic treatment response, and exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov registration: NCT03763240.
Evaluating personal care product use by Environmental Working Group hazard scores in relation to consumers’ sociodemographic characteristics, purchasing behaviors, and product safety perceptions
Personal care products (PCPs) are a source of environmental chemical exposures. Little research has examined the specific PCPs people use, the environmental hazards posed by those PCPs, and factors informing PCP selection.
TIR1-produced cAMP as a second messenger in transcriptional auxin signalling
The phytohormone auxin (Aux) is a principal endogenous developmental signal in plants. It mediates transcriptional reprogramming by a well-established canonical signalling mechanism. TIR1/AFB auxin receptors are F-box subunits of an ubiquitin ligase complex; after auxin perception, they associate with Aux/IAA transcriptional repressors and ubiquitinate them for degradation, thus enabling the activation of auxin response factor (ARF) transcription factors1,2,3. Here we revise this paradigm by showing that without TIR1 adenylate cyclase (AC) activity4, auxin-induced degradation of Aux/IAAs is not sufficient to mediate the transcriptional auxin response. Abolishing the TIR1 AC activity does not affect auxin-induced degradation of Aux/IAAs but renders TIR1 non-functional in mediating transcriptional reprogramming and auxin-regulated development, including shoot, root, root hair growth and lateral root formation. Transgenic plants show that local cAMP production in the vicinity of the Aux/IAA–ARF complex by unrelated AC enzymes bypasses the need for auxin perception and is sufficient to induce ARF-mediated transcription. These discoveries revise the canonical model of auxin signalling and establish TIR1/AFB-produced cAMP as a second messenger essential for transcriptional reprograming.
Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men
Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.
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