The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis.

Abstract.(1) A preparation is described which allows patch clamp recordings to be made on mammalian central nervous system (CNS) neurones in situ. (2) A vibrating tissue slicer was used to cut thin slices in which individual neurones could be identified visually. Localized cleaning of cell somata with physiological saline freed the cell membrane, allowing the formation of a high resistance seal between the membrane and the patch pipette. (3) The various configurations of the patch clamp technique were used to demonstrate recording of membrane potential, whole cell currents and single channel currents from neurones and isolated patches. (4) The patch clamp technique was used to record from neurones filled with fluorescent dyes. Staining was achieved by filling cells during recording or by previous retrograde labelling. (5) Thin slice cleaning and patch clamp techniques were shown to be applicable to the spinal cord and almost any brain region and to various species. These techniques are also applicable to animals of a wide variety of postnatal ages, from newborn to adult.

Distinct classes of acetylcholine receptor channels are formed when Xenopus oocytes are injected with combinations of the bovine alpha-, beta-, gamma- and delta- or the alpha-, beta-, gamma- and epsilon-subunit-specific messenger RNAs. The conductance and gating properties of the two classes of channels, in conjunction with the developmental changes in the muscular contents of the mRNAs, suggest that replacement of the gamma-subunit by the epsilon-subunit is responsible for the functional alteration of the receptor during muscle development.

Synaptic transmission is mediated by calcium entry through voltage-dependent calcium channels in presynaptic nerve terminals. Various types of calcium channel have been characterized in neuronal somata, but it is not clear which subtypes induce transmitter release at central synapses. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTx) suppresses the excitatory postsynaptic responses only partially, whereas potassium-induced release of glutamate from brain synaptosomes can be blocked by omega-Aga-VIA (ref. 9), a blocker of P-type calcium channels and possibly of other types of calcium channels. Here we test type-specific calcium-channel blockers on postsynaptic currents recorded from neurons in thin slices of rat central nervous system. Inhibitory postsynaptic currents in cerebellar and spinal neurons and excitatory postsynaptic currents in hippocampal neurons are markedly suppressed by omega-Aga-IVA and reduced to a lesser extent by omega-CgTx. The L-type calcium channel blocker nicardipine had no effect. Our results indicate that at least two types of calcium channel mediate synaptic transmission in the mammalian central nervous system.